Substituted naphthylenes for the treatment of non-insulin dependent diabetes mellitus

ABSTRACT

This invention provides compounds of formula I, having the structure 
                 
 
wherein R 1 , R 4 , A, and Z are as defined in the specification, or a pharmaceutically acceptable salt thereof, that are useful in treating metabolic disorders mediated by insulin resistance or hyperglycemia.

This application claims the benefit under 35 U.S.C §119(e) to U.S.provisional application Ser. No. 60/371,373 filed Apr. 10, 2002, whichis hereby incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

This invention relates to novel compounds of general formula I orpharmaceutically acceptable salts thereof, which lower plasma glucoselevels and/or insulin levels in vivo and/or inhibit the production ofPEPCK enzyme and/or lower glucose and/or insulin levels in culturedcells and are therefore useful in the treatment of non-insulin dependentdiabetes mellitus (NIDDM).

Diabetes mellitus is a syndrome characterized by abnormal insulinproduction, increased urinary output and elevated blood glucose levels.There are two major subclasses of diabetes mellitus. One is theinsulin-dependent diabetes mellitus (IDDM or Type 1), formerly referredto as juvenile onset diabetes since it was evident early in life, andnon-insulin dependent diabetes mellitus (NIDDM or Type 2), oftenreferred to as maturity-onset diabetes. Exogenous insulin by injectionis used clinically to control diabetes but suffers from severaldrawbacks. Insulin is a protein and thus cannot be taken orally due todigestion and degradation but must be injected. It is not alwayspossible to attain good control of blood sugar levels by insulinadministration. Insulin resistance sometimes occurs requiring muchhigher doses of insulin than normal. Another shortcoming of insulin isthat while it may control hormonal abnormalities, it does not alwaysprevent the occurrence of complications such as neuropathy, retinopathy,glomerulosclerosis, or cardiovascular disorders. Insulin regulatesglucose homeostasis mainly by acting on two targets tissues: liver andmuscle. Liver is the only site of glucose production and skeletal musclethe main site of insulin mediated glucose uptake.

Orally effective antihyperglycemic agents are used to reduce bloodglucose levels and to reduce damage to the nervous, retinal, renal orvascular systems through mechanisms affecting glucose metabolism. Suchagents act in a variety of different mechanisms including inhibition offatty acid oxidation, a-glycosidase inhibition, antagonism ofa₂-receptors and inhibition of gluconeogenesis. Two classes of compoundshave predominated: the biguanides as represented by phenformin and thesulfonylureas as represented by tolbutamide (Orinase®). A third class ofcompounds which has shown antihyperglycemic activity are thethiazolidinediones. Recently a member (troglidazone) of this family wasintroduced for the treatment of Type 2 diabetes.

PEPCK is present at relatively high specific activity in liver, renalcortex, and white fat (R. M. O'Brien, Diabetes Care, 1990, 13, 327-339).It catalyzes the conversion of oxaloacetate to phosphonoenolpyruvate,the rate-limiting step in hepatic and renal gluconeogenesis, and it isessential for the synthesis of a-glycerophosphate in adipose tissue.Given that PEPCK catalyzes the rate-limiting step in gluconeogenesis, itis reasonable to conclude that the activity of the PEPCK gene determinesthe rate of this important metabolic process (E. Sharfir, Frontiers InDiabetes Research, 1998, John Libbey & Company, Ltd, pp 304-315). PEPCKactivity is altered in vivo by glucagon, glucocorticoids, insulin,epinephrine, thyroxine and glucose. The primary effectors are glucagonand glucocorticoids, which increase the synthesis of PEPCK, and insulin,which decreases its synthesis. All of these effects appear to resultfrom alterations in the amount of PEPCK mRNA, which in turn result fromchanges in the rate of transcription of the PEPCK gene. Gluconeogenesisrates are increased two- to three-fold in patients with NIDDM, andgluconeogenesis is the predominant mechanism responsible for fastinghyperglycemia in NIDDM (A. Consoli, et.al. Diabetes, 1989, 38, 550-557).Modulation of the transcription of the PEPCK gene may lead to glucoselowering in NIDDM patients.

Clinical Correlation: Compounds that inhibit or modulate glucoseproduction in cultured hepatocytes from gluconeogenic precursors shouldinhibit gluconeogenesis in man and cause a reduction in the circulatingplasma glucose level. Known gluconeogenic inhibitors that causedecreases in blood glucose in vivo have been shown to be active in thisassay. (References: Berry M N, Edwards A M, Barritt G J. Isolatedhepatocytes, preparation properties and applications in laboratorytechniques in Biochemistry and Molecular Biology. 1983;65:55-63; Exton,J. H. The perfused rat liver in Methods in Enzymology XXXIX, part D(Hormone Action), pp 25-36 (1975). Eds.; J. G. Hardman and B. W.O'Malley. Goodman M N. Effect of 3-mercaptopicolinic acid ongluconeogenesis and gluconeogenic metabolite concentrations in theisolated perfused rat liver. Biochem. J. 1975;150:137-139; Jomain-BaumM, Schramm V L, Hanson R W. Mechanism of 3-mercaptopicolinic acidinhibition of hepatic phosphoenol pyruvate carboxykinase (GTP). J. Biol.Chem. 1976;251:37-44; Lowry O H, Rosebrough N J, Farr A L, Randall R J:Protein measurement with the Folin phenol reagent. J. Biol. Chem.1951;193:265-275; Musmann T. Rapid calorimetric assay for cellulargrowth and survival: application to proliferation and cytotoxicityassays. J. Immunol. Meth. 1983;65: 55-63).

DESCRIPTION OF THE INVENTION

The compounds of the present invention, represented by Formula I below,act to inhibit the production of PEPCK enzyme and/or PEPCK mRNA, and/orlower glucose and/or insulin levels in cultured cells, and/ordemonstrate oral antihyperglycemic activity in an animal model of NIDDM,namely the ob/ob mouse, and are useful in the treatment of non-insulindependent diabetes mellitus (NIDDM).

wherein:

-   Z is-   Y is selected from O, S, N, C═C, or C═N;-   R₁ is selected from —SO₂CF₃, —SO₂Ar, —SO₂CH₃, —SO₂CH₂CF₃, —CONH₂,    —CSNHCH₃, —CONHAr, —COAr, —COCCl₃;-   Ar is phenyl, naphthyl, pyridyl, or quinolyl, which may be    optionally mono- or di-substituted with alkyl of 1-6 carbon atoms,    alkenyl of 2-7 carbon atoms, halogen, hydroxyl, alkoxy of 1-6 carbon    atoms, —CN, —NO₂, amino, alkylamino of 1-6 carbon atoms,    dialkylamino of 1-6 carbon atoms per alkyl group, thio, alkylthio of    1-6 carbon atoms, alkylsulfinyl of 1-6 carbon atoms, alkylsulfonyl    of 1-6 carbon atoms, alkoxycarbonyl of 2-7 carbon atoms,    alkylcarbonyl of 2-7 carbon atoms, or benzoyl;-   R₂ and R₃ are independently selected from hydrogen, halogen,    hydroxy, -alkoxy of 1-6 carbon atoms, —CF₃, —CN, alkyl of 1-6 carbon    atoms, or —CH═CHPh; or R₂ and R₃ may be taken together as    —C(CH₃)₂CH₂CH₂—C(CH₃)₂—, or —OCH₂CH₂O—; or R₂ and R₃ may be taken    together as —CH═CH—CH═CH—, when A is not a bond;-   R₄ is hydrogen or halogen,-   A is a bond; or-    wherein R₆, and R₇ are each, independently, hydrogen, hydroxy,    alkoxy of 1-6 carbon atoms, CF₃, CN, or alkyl of 1-6 carbon atoms;-    R₈ is hydrogen or alkyl of 1-6 carbon atoms;    or a pharmaceutically acceptable salt form thereof.

Pharmaceutically acceptable salts can be formed from organic andinorganic acids, for example, acetic, propionic, lactic, citric,tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic,hydrochloric, hydrobromic, phosphoric, nitric, sulfuric,methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic,camphorsulfonic, and similarly known acceptable aids when a compound ofthis invention contains a basic moiety. Salts may also be formed fromorganic and inorganic bases, such as alkali metal salts (for example,sodium, lithium, or potassium) alkaline earth metal salts, ammoniumsalts, alkylammonium salts containing 1-6 carbon atoms ordialkylammonium salts containing 1-6 carbon atoms in each alkyl group,and trialkylammonium salts containing 1-6 carbon atoms in each alkylgroup, when a compound of this invention contains an acidic moiety.

The term alkyl includes both branched and straight chain moieties.Examples include methyl, ethyl, propyl, butyl, isopropyl, sec-butyl,tert-butyl and the like. The term halogen includes bromine, chlorine,fluorine, and iodine. The term alkylthio means —S-alkyl.

As used in accordance with this invention, the term “providing,” withrespect to providing a compound or substance covered by this invention,means either directly administering such a compound or substance, oradministering a prodrug, derivative, or analog which will form theeffective amount of the compound or substance within the body.

A first group of preferred compounds of the present invention are thoseof formula II:

wherein,

-   A is-   Y is —C═C—;    or a pharmaceutically acceptable salt form thereof.

A second group of preferred compounds of this invention are those offormula (III):

or a pharmaceutically acceptable salt form thereof.

A third group of preferred compounds of this invention comprises thoseof formulae (IV and (V):

wherein:

R₁ is selected from SO₂CF₃, SO₂Ar, SO₂CH₃, SO₂CH₂CF₃, CONH₂, CSNHCH₃,CONHAr, COAr, or COCCl₃;

Ar represent an optionally mono- or di-substituted phenyl, naphthyl,pyridyl, or quinolyl group; and

R₂ and R₃ are independently selected from the group of H, Cl, Br, F,OCH₃, CF₃, CN, or CH₃; or a pharmaceutically acceptable salt formthereof.

A fourth preferred group of compounds of this invention are those offormulae (VI) and (VII):

wherein:

represents a group selected from:

or a pharmaceutically acceptable salt form thereof.

A fifth group of preferred compounds of this invention includes those offormula VIII:

or a pharmaceutically acceptable salt form thereof.

Particularly preferred compounds of this invention are:

-   -   a)        C,C,C-Trifluoro-N-[5-biphenyl-3-ylmethoxy)-naphthalen-2-yl]-methanesulfonamide;    -   b)        N-[5-(3′,4′-Dichloro-3-fluoro-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-C,C,C-trifluoro-methanesulfonamide;    -   c)        N-[5-(4-naphthalen-2-yl-benzyloxy-3-ylmethoxy)-naphthalen-2-yl]-C,C,C-trifluoro-methanesulfonamide;    -   d)        C,C,C-Trifluoro-N-[5-(3-fluoro-4′-trifluoromethyl-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-methanesulfonamide;    -   e)        N-[5-(4′-tert-Butyl-3-fluoro-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-C,C,C-trifluoro-methanesulfonamide;    -   f)        N-[5-(3,4′-Dichloro-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-C,C,C-trifluoro-methanesulfonamide;    -   g)        C,C,C-Trifluoro-N-[5-(3,3′,4′-trichloro-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-methanesulfonamide;    -   h)        N-{5-[2-(2,4-Difluoro-phenyl)-thiazol-4-ylmethoxy]-naphthalen-2-yl}-C,C,C-trifluoro-methanesulfonamide;    -   i)        C,C,C-Trifluoro-N-{5-[2-(5-trifluoromethyl-pyridin-2-yl)-thiazol-4-yl-methoxy]naphthalen-2-yl}-methanesulfonamide;    -   j)        C,C,C-Trifluoro-N-{5-[2-(4-methoxy-phenyl)-thiazol-4-ylmethoxy]-naphthalen-2-yl}-methanesulfonamide;    -   k)        N-{5-[2-(4-trufluoromethyl-phenyl)-thiazol-4-ylmethoxy]-naphthalen-2-yl}-C,C,C-trifluoro-methanesulfonamide;    -   l)        C,C,C-Trifluoro-N-[5-(3-fluoro-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-methanesulfonamide;        or    -   m)        N-{5-[5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-ylmethoxy]naphthalen-2-yl}C,C,C-trifluoromethanesulfonamide

The reagents used in the preparation of the compounds of this inventioncan be either commercially obtained or can be prepared by standardprocedures described in the literature. The compounds of the presentinvention can be generally prepared according to the following syntheticscheme.

The synthesis of the title products is depicted in Scheme I. Aminoalcohols of type (II) are reacted with a halo compound of type (III)(prepared as described or obtained from commercial sources) in thepresence of a strong base and crown ether to provide the coupled productof type (IV). This intermediate is then reacted with the appropriateelectrophile to provide the title compounds (I). These processes arewell known in the art.

The compounds of this invention are useful in treating metabolicdisorders related to insulin resistance or hyperglycemia, typicallyassociated with obesity or glucose intolerance. The compounds of thisinvention are therefore, particularly useful in the treatment orinhibition of type II diabetes. The compounds of this invention are alsouseful in modulating glucose levels in disorders such as type Idiabetes. Additionally, because an association exists between insulinresistance and hypertension and between insulin resistance, hypertensionand coronary artery disease, the compounds of this invention are alsouseful for the treatment of primary (essential) hypertension andatherosclerosis.

The ability of compounds of this invention to treat or inhibit disordersrelated to insulin resistance or hyperglycemia was established withrepresentative compounds of this invention in the followingpharmacological test procedures.

Inhibition of Glucose Output from Hepatocytes Isolated and Cultured fromObese Zucker (fa/fa) Rats and Their Lean Controls

Culturing of Hepatocytes: Isolated hepatocytes were plated on 12 wellrat-tail collagen coated plates at a cell density of 5×10(5) cells/ml(approximately 1 ml of cell suspension per well). Following a one hourattachment period in which plates were incubated in a CO₂ incubator at37 deg C. (95% O₂, 5% CO₂), the supernatant containing unattachedhepatocytes was removed and replaced with fresh media (1 ml/well)containing 1 μM dexamethasone and 100 pM insulin. Cells were maintainedat 37 deg C. for 48 hours in a 95% O₂, 5% CO₂ environment. At the end ofthe first 24 hours, the media was aspirated off of the wells andreplaced with fresh media containing the same concentrations ofdexamethasone and insulin as described earlier. Treatment with Drugs andAssessment of Glucose Output: Drugs were routinely added with freshmedia 24 hours after the initial attachment period. Eighteen hourslater, media was aspirated and 500 μl of fresh Hank's buffer, Buffer D(glucose-free) supplemented with hormones, gluconeogenic substrates anddrug(s) was added to each well and incubated for 4 hours. At the end ofthe 4 hour incubation, media from each well was removed and assayed forglucose content using the hexokinase/glucose-6-phosphate dehydrogenasecoupled assay on the Boehringer Mannheim model 911 auto analyzer.Glucose concentration was expressed as μg/ml. Three of the plates fromeach treated group were frozen for subsequent determination of proteincontent. Two plates from each treatment group were used to assess thecytotoxicity of drug(s) and other agents as determined by the MTT(tetrazolium) dye reduction method (see below).

Assessment of Cytotoxicity using MTT Dye Reduction Assay: Two plateswith no insulin treatment and two plates with 10⁻⁸ M insulin treatmentwere used for the MTT dye reduction assay. Following removal of mediafrom the plates for measurement of glucose output, wells were washedonce with 1 ml of Hank's buffer (0.5% BSA). Aliquots of 500 ml of Hank'sbuffer (1.1% BSA) and 50 ml MTT solution (5 mg MTT/ml in phosphatebuffered saline (PBS) filtered through 0.45 micron syringe filter) wereadded to each well. Plates were incubated for one hour at 37 deg C.After one hour incubation, the MTT dye solution was aspirated off and300 ml of HCL/isopropanol solution (8 ml of 1N HCL and 192 ml ofisopropanol) was added to each well. HCL/isopropanol solution was mixedby drawing liquid into a pipetman 2 to 3 times and then carefullytransferred into a 96 well flat bottom plate. The 96 well plate was readon a plate reader (UV max kinetic microplate reader, Molecular Devices)at 570 nm test wavelength and 650 nm reference wavelength. The resultswere expressed as % inhibition from the control (lactate and glucagontreated) well.

Protein test procedure: Three plates with no insulin treatment and threeplates with 10⁻⁸ M insulin treatment were used for proteindetermination. After supernatant has been removed for determination ofglucose output the plates were frozen and stored at −20 deg C. untilready to assay for protein content. Prior to determination of proteinthe plates were defrosted at room temperature for 15 minutes. An aliquotof 1 ml 0.1 N NaOH was added to each well. Plates were incubated at 4deg C. overnight. Solutions for measurement of protein content weremixed by pipetting the NaOH solution up and down several time with a 1ml pipette and then transferring to a small polyethylene tube. Proteindetermination was based on that of the Pierce BCA protein assay protocol(Pierce cat. no. 23223). A set of protein standards (0.2, 0.4, 0.6, 0.8,and 1 mg/ml BSA) was prepared by serial dilution of 1 mg/ml bovine serumalbumin with 0.1 N NaOH, and 40 μl of each standard, or control blankwas pipetted into a 96-well plate in duplicate. Each unknown proteinsample (40 μl) was tested in triplicate. An aliquot of 200 μl of BCAprotein assay reagent (consisting of 50 parts Reagent A with 1 partReagent B) was added to each well. Samples were mixed with a Titertekpipette. The microtiter plate was covered with sealing tape andincubated at room temperature for 1 hour. After incubation, the sealingtape was removed and absorbance measured on a plate reader (Uvmaxkinetic microplate reader, Molecular Devices) at 570 nm. A standardcurve was prepared by plotting the blank-corrected absorbance againstknown protein concentrations, and protein concentrations were thendetermined for each unknown.

Buffers: Buffer A   50 ml 10XHBSS   400 ml ddH2O  2.38 g Hepes   95 mgEGTA   900 mg glucose  2.36 ml 7.5% NaHCO₃ pH to 7.4 with 1 N NaOH q.s.to 500 ml with ddH₂O qs to 2L Buffer B   50 ml 10XHBSS   430 ml ddH₂O 2.45 mg Hepes 366.3 mg CaCl₂.2H₂O   891 mg glucose  2.34 ml 7.5% NaHCO₃qs to 500 ml   100 mg collagenase Buffer C (10 × solv.)  1800 ml ddH2O  95.2 g Hepes  142.6 g NaCl  7.5 g KCL  4.8 g MgSO₄  11.4 g K₂HPO₄.3H₂OBuffer D   50 ml 10 × Buffer C   400 ml ddH₂O   59 mg CaCl₂.2H₂O  1.01 gNaHCO₃ BSA (0.2-1.1%) if necessary pH to 7.4 qs to 500 ml

Measurements and Calculations: Glucose output was calculated as μgglucose/mg protein/hour, and inhibition of glucose output was calculatedas percent inhibition of glucose output when compared to glucagonstimulated cells. Cytotoxicity was determined using the MTT dyereduction assay and data were expressed as percent inhibition of MTT dyereduction compared to control cells. For some compounds of interestmultiple point dose response curves were assessed and half-maximalinhibitory concentrations (IC₅₀) were calculated for both inhibition ofglucose output and MTT dye reduction. Insulin potentiation was assessedby calculating the difference in percent inhibition of glucose outputwith and without drug(s) in the presence of the same insulinconcentration.

Statisical Analysis: Two factors ANOVA with interaction was used tocompare different compounds to control and other compounds within eachconcentration of insulin. The same procedure was used to compare effectsof insulin alone. The ICx (where x equals 25,50 etc.) was determined forinsulin, drug and insulin+drug using multi point logistic four parameterdose response curves. In addition another parameter (insulin interactionwith drug) was estimated using the same technique. Confidence intervals(Wald) were determined using student's t distribution.

Reference Compound: Mercaptopicolinc acid (inhibitor of PEPCK activity)

References:

Berry M N, Edwards A M, Barritt G J. Isolated hepatocytes, preparationproperties and applications in laboratory techniques in Biochemistry andMolecular Biology. 1983;65:55-63.

Exton, J H. The perfused rat liver in Methods in Enzymology XXXIX, partD (Hormone Action), pp 25-36 (1975). Eds. J. G. Hardman and B. W.O'Malley.

Goodman M N. Effect of 3-mercaptopicolinic acid on gluconeogenesis andgluconeogenic metabolite concentrations in the isolated perfused ratliver. Biochem. J. 1975;150:137-139,

Jomain-Baum M, Schramm V L, Hanson R W. Mechanism of 3-mercaptopicolinicacid inhibition of hepatic phosphoenol pyvrate carboxykinase (GTP). J.Biol. Chem.

Musmann T. Rapid colorimetric assay for cellular growth and survival:application to proliferation and cytotoxicity assays. J. Immunol. Meth.1983;65:55-63.

Smith P K, Krohn R I, Hermanson G T, Mallia A K, Gartner F H, ProvenjanoM D, Fujimoto E K, Goeke N M, Olson B J, and Klenk D C. Measurement ofProtein Using Bincinchoninic Acid. Analo. Biochem. 1985;150:76-85.

The following table summarizes the results obtained using representativecompounds of this invention.

EXAMPLE IC₅₀ 5  6.3 μM 14 10.4 μM 27  7.0 μM 30  3.1 μM 31  2.6 μM 46 2.8 μM 52   12 μM 53  9.5 μM 57  1.5 μM

Hypoglycemic Effect in Diabetic OB/OB Mice

Procedure: In each study, male or female ob/ob (C57 B1/6J) mice andtheir mean litermates (ob/+ or +/+, Jackson Laboratories) ages 2 to 5months (10 to 65 g) were randomized according to plasma glucose into 4groups of 10 mice. The mice were housed 5 per cage and were maintainedon normal rodent chow with water ad libitum. Mice receive compound dailyby gavage (suspended in 0.5 ml of 0.5% methyl cellulose); dissolved inthe drinking water; or admixed in the diet. The dose of compounds givenranges from 2.5 to 200 mg/kg body weight/day. Body weight of fed animalswas measured at the beginning of each week and doses for the entire weekwere calculated using this weight and were expressed in terms of theactive moiety of the compound. Control mice receive vehicle only.

On the morning of Day 4, 7 or 14 two drops of blood (approximately 50ul) were collected into sodium fluoride containing tubes either from thetail vein or after decapitation. For those studies in which the compoundwas administered daily by gavage the blood samples were collected fourhours after compound administration.

Measurements: The plasma was isolated by centrifugation and theconcentration of glucose was measured enzymatically on an Abbott V. P.Analyzer and the plasma concentration of insulin was determined byradioimmunoassay (Heding, 1972)

Calculations: For each mouse, the percentage change in plasma glucose onDay 4, 7 or 14 was calculated relative to the mean plasma glucose of thevehicle treated mice. Analysis of variance followed by Dunnett'sComparison Test (one-tailed) was used to estimate the significantdifference between the plasma glucose values from the control group andthe individual compound treated groups (CMS SAS Release 5.18). Acompound will be considered active if the difference has a p<0.05.

Clinical Correlation: The non-insulin dependent diabetic (NIDDM)syndrome can be typically characterized by obesity, hyperglycemia,abnormal insulin secretion, hyperinsulinemia and insulin resistance. Thegenetically obese-hyperglycemic ob/ob mouse exhibits many of thesemetabolic abnormalities and is a useful model for hypoglycemic agents totreat NIDDM (Coleman, 1978).

Reference Compound: Ciglitazone(5-(4-(1-methylcyclohexylmethoxy)-benzyl)-2,4-dione, Upjohn) and sodiummetavanadate (NaVO3) at doses of 100 and 20 mg/kg/day, respectively,produce a significant lowering in plasma glucose (Brichard et al. 1990;Chang et al. 1983.

References:

Brichard, S., Bailey, C. and Henquin, J.: Marked improvement of glucosehomeostasis in diabetic ob/ob mice given oral vanadate Diabetes 39:1326-1332,1990.

Chang, A., Wyse, B., Gilchrist, B., Peterson, T. and Diani, A.:Ciglitazone, a new hypoglycemic agent. I. Studies in ob/ob and db/dbmice, diabetic Chinese hamsters, and normal and streptozotocin-diabeticrats. Diabetes 32: 830-838,1983.

Coleman, D.: Obese and diabetes: Two mutant genes causingdiabetes-obesity syndromes in mice. Diabetologia 14: 141-148,1978.

Heding, L. G.: Determination of total serum insulin (IRI) ininsulin-treated diabetic patients. Diabetologia 8:260-266, 1972.

The following table summarizes the results obtained using representativecompounds of this invention.

REDUCTION IN PLASMA GLUCOSE EXAMPLE Day 1 (6 hr) p.o. Day 3 (6 hr) p.o.27 −31% (10 mg/kg) 30  −6% (25 mg/kg) −11% (25 mg/kg) 57 −33% (10 mg/kg)4 −28% (10 mg/kg) −37% (10 mg/kg) 31 −23% (5 mg/kg) −22% (5 mg/kg) 25−22% (10 mg/kg) −24% (10 mg/kg) 81 −28% (5 mg/kg) −33% (5 mg/kg)

Based on the results obtained in the standard pharmacological testprocedures, the compounds of this invention are useful in treatingmetabolic disorders related to insulin resistance or hyperglycemia,typically associated with obesity or glucose intolerance. Moreparticularly, the compounds of this invention are useful in thetreatment or inhibition of type II diabetes, and in modulating glucoselevels in disorders such as type I diabetes. The compounds of thisinvention are also useful in the treatment of primary (essential)hypertension and atherosclerosis. As used herein, the term modulatingmeans maintaining glucose levels within clinically normal ranges.

Effective administration of these compounds may be given at a dailydosage of from about 1 mg/kg to about 250 mg/kg, and may given in asingle dose or in two or more divided doses. Such doses may beadministered in any manner useful in directing the active compoundsherein to the recipient's bloodstream, including orally, via implants,parenterally (including intravenous, intraperitoneal and subcutaneousinjections), rectally, vaginally, and transdermally. For the purposes ofthis disclosure, transdermal administrations are understood to includeall administrations across the surface of the body and the inner liningsof bodily passages including epithelial and mucosal tissues. Suchadministrations may be carried out using the present compounds, orpharmaceutically acceptable salts thereof, in lotions, creams, foams,patches, suspensions, solutions, and suppositories (rectal and vaginal).

Compounds of this invention may be administered neat or with apharmaceutical carrier to a patient in need thereof. The pharmaceuticalcarrier may be solid or liquid.

Oral formulations containing the active compounds of this invention maycomprise any conventionally used oral forms, including tablets,capsules, buccal forms, troches, lozenges and oral liquids, suspensionsor solutions. Capsules may contain mixtures of the active compound(s)with inert fillers and/or diluents such as the pharmaceuticallyacceptable starches (e.g. corn, potato or tapioca starch), sugars,artificial sweetening agents, powdered celluloses, such as crystallineand microcrystalline celluloses, flours, gelatins, gums, etc. Usefultablet formulations may be made by conventional compression, wetgranulation or dry granulation methods and utilize pharmaceuticallyacceptable diluents, binding agents, lubricants, disintegrants,suspending or stabilizing agents, including, but not limited to,magnesium stearate, stearic acid, talc, sodium lauryl sulfate,microcrystalline cellulose, carboxymethylcellulose calcium,polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, xanthan gum,sodium citrate, complex silicates, calcium carbonate, glycine, dextrin,sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose,kaolin, mannitol, sodium chloride, talc, dry starches and powderedsugar. Oral formulations herein may utilize standard delay or timerelease formulations to alter the absorption of the active compound(s).Suppository formulations may be made from traditional materials,including cocoa butter, with or without the addition of waxes to alterthe suppository's melting point, and glycerin. Water soluble suppositorybases, such as polyethylene glycols of various molecular weights, mayalso be used.

It is understood that the dosage, regimen and mode of administration ofthese compounds will vary according to the malady and the individualbeing treated and will be subject to the judgment of the medicalpractitioner involved. It is preferred that the administration of one ormore of the compounds herein begin at a low dose and be increased untilthe desired effects are achieved.

The following procedures describe the preparation of representativeexamples of this invention.

EXAMPLE 1N-[5-(4-Bromo-benzyloxy)-naphthalen-2-yl}-C,C,C-trifluoromethanesulfonamide

Step 1. Preparation of5-(Bromo-phenyl-4-ylmethoxy)-naphthalen-2-yl-amine

General Procedure for Ether Coupling

To a solution of 0.30 g (12.5 mmol) of 95% sodium hydride in 50 ml ofTHF was added dropwise a 50 mL solution of 1.59 g (10 mmol) of6-amino-1-naphthol at 0° C. 1 drop of 15-crown-5 and/or DMSO was thenadded, and after stirring for 0.5 hr 2.7 g (13 mmol) of 4-bromobenzylchloride was added in one portion. The mixture was stirred at roomtemperature for 5 hr. At the end of this time, the solution wasconcentrated and the residue washed with 15 ml of saturated ammoniumchloride and extracted 2 times with 30 mL of ethyl acetate. The organiclayers were combined, dried (MgSO₄) and concentrated. The crude solidwas chromatographed on silica gel eluting with 40% ethyl acetate:hexane.Concentration yielded 1.91 g (62%) of the product as a brown solid, usedin the next step without further purification.

NMR (200 Mhz, CDCl₃) δ 8.17 (d, J=8 Hz, 1H ArH), 7.56 (d, J=8 Hz, 2H,ArH), 7.38 (d, J=8 Hz, 2H, ArH), 7.25 (m, 2H, ArH), 6.91 (m, 2H, ArH),6.61 (d, J=8 Hz, 1H, H6), 5.15 (s, 2H, OCH2), 3.84 (bs, 2H, NH).

Step 2. Preparation of the Title Compound

General Procedure for Triflation of Amines

To a 250 mL flask charged with 150 mL of methylene chloride is added1.03 mL (7.41 mmol) of triethyl amine and 1.89 g (6.18 mmol) of theproduct from Step 1. The flask was cooled to −20° C. where upon asolution of 1.14 mL (6.80 mmol) of trifluoromathane sulfonic anhydridein 25 mL of methylene chloride was added dropwise under nitrogenatmosphere. After ½ hr, 2 mL of a 1M solution tetra n-butyl ammoniumflouride was added and the mixture stirred for 16 hr. At the end of thistime, the solution was concentrated, diluted with 50 mL of saturatedammonium chloride and extracted 2 times with ethyl acetate. The organiclayers were combined, dried (MgSO₄) and concentrated. The crude solidwas chromatographed on silica gel eluting with 30% ethyl acetate:hexane.Concentration yielded 1.83 g (68%) of the title compound as a brown oil,used in the next step without further purification.

NMR (400 MHz, DMSO-d6) δ 11.80 (bs, 1H, NH), 7.45 (d, J=8 Hz, 2H ArH),7.18 (d, J=8 Hz, 2H, ArH), 7.7 (t, J=8 Hz, 1H, H5), 7.17 (d, J=8 Hz, 1H,H4), 7.15 (s, 1H, H2), 7.11 (d, J=8 Hz, 1H, H6), 4.51 (s, 2H, OCH2),3.65 (t, J=7 Hz, 2H, OCH2), 2.85 (t, J=7 Hz, 2H, ArCH2).

EXAMPLE 2N-[5-(3′,4′-Dichloro-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-C,C,C-trifluoro-methanesulfonamide

General Procedure for Aryl Coupling

To a 50 mL flask charged with 20 mL toluene and 5 mL EtOH was added 250mg (0.57 mmol) of the product from Example 1, 153 mg (0.80 mmol) of3,4-dichloro benzene boronic acid, and 3 mL of aqueous 5% potassiumcarbonate solution. The flask was stirred and degassed for 5 minuteswith a steady stream of nitrogen, after which 35 mg (0.03 mmol) oftetrakis(triphenylphosphine) palladium(0) was added. The mixture washeated to 70° C. for 18 hr under an atmosphere of nitrogen. At the endof this time the solution was concentrated and diluted with 30 mL ofsaturated ammoniun chloride solution. The mixture was extracted 2× withethyl acetate and the organic layers combined and dried (MgSO₄), thenconcentrated. The crude solid was chromatographed on silica gel elutingwith 30% ethyl acetate:hexane. Concentration yielded 0.192 mg (68%) ofthe title compound as an oil, which was triturated with hexane to form asolid. The solid was recrystallized from ethyl acetate:hexane to yield0.17 g of the title product as colorless crystals, m.p. 98-100° C.

NMR (400 MHz, DMSO-d6) δ 11.80 (bs, 1H, NH), 8.24 (d, J=8 Hz, 1H, H8),7.93 (s, 1H, H1), 7.62-7.98 (m, 7H, ArH), 7.36-7.51 (m, 3H, ArH), 7.18(d, J=8 Hz, 1H, H3), 5.38 (s, 2H, OCH2).

Anal. Calcd. for C24H16C12F3N1O3S1: C, 54.76; H, 3.06; N, 2.66. Found:C, 54.28; H, 3.22; N, 2.57.

C,C,C-Trifluoro-N-[5-(4′-methoxy-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-methanesulfonamide,165-167° C.,

NMR (400 MHz, DMSO-d6) δ11.80 (bs, 1H, NH), 8.22 (d, J=8 Hz, 1H, H8),7.77 (s, 1H, H1), 7.53-7.69 (m, 6H, ArH), 7.38-7.55 (m, 3H, ArH), 7.18(d, J=8 Hz, 1H, H3), 7.04 (d, J=8 Hz, 2H, ArH), 5.36 (s, 2H, OCH2), 3.81(s, 3H, OCH3).

Anal. Calcd. for C25H20F3N1O4S1: C, 61.60; H, 4.13; N, 2.87. Found: C,61.41; H, 4.33; N, 2.73.

EXAMPLE 3C,C,C-Trifluoro-N-[5-(2-fluoro,4-bromophen-2-yl-methoxy)-naphthalen-2-yl]-methanesulfonamide

Step 1. Preparation of5-(2-fluoro,4-bromophen-2-yl-methoxy)-naphthalen-2-yl-amine

To a solution of 0.30 g (12.5 mmol) of 95% sodium hydride and 1 drop of15-crown-5 in 150 mL of THF was added dropwise a solution of 1.59 g (10mmol) of 6-amino-1-naphthol at 0° C. After stirring for 0.5 hr 2.8 g (13mmol) of 4-bromo,2-fluoro benzyl bromide was added in one portion. Themixture was stirred at room temperature for 5 hr. At the end of thistime, the solution was concentrated and the residue washed with 10 ml ofsaturated ammonium chloride and extracted 2 times with 40 mL of ethylacetate. The organic layers were combined, dried (MgSO₄) andconcentrated. The crude solid was chromatographed on silica gel elutingwith 40% ethyl acetate:hexane. Concentration yielded 2.2 g (65%) of theproduct as a brown solid, used in the next step without furtherpurification.

Step 2. Preparation of the Title Compound

To a 250 mL flask charged with 150 mL of methylene chloride is added 1.1mL (7.92 mmol) of triethyl amine and 2.2 g (6.60 mmol) of the productfrom Step 1. The flask was cooled to −20° C. where upon a solution of1.2 mL (7.92 mmol) of trifluoromathane sulfonic anhydride in 25 mL ofmethylene chloride was added dropwise under nitrogen atmosphere. After ½hr, 2 mL of a 1M solution tetra n-butyl ammonium flouride was added andthe mixture stirred for 16 hr. At the end of this time, the solution wasconcentrated, diluted with 50 mL of saturated ammonium chloride andextracted 2 times with ethyl acetate. The organic layers were combined,dried (MgSO₄) and concentrated. The crude solid was chromatographed onsilica gel eluting with 30% ethyl acetate:hexane. Concentration yielded1.8 g (68%) of the title compound as a brown solid. The product can berecrystallized from ethyl acetate:hexane to yield 0.87 of light brownsolid, m.p. 126-128° C.

NMR (200 MHz, CDCl3) δ 11.80 (bs, 1H, NH), 8.32 (d, J=8 Hz, 1H, H8),7.72 (s, 1H, H1), 7.23-7.53 (m, 6H, ArH), 6.73 (d, J=8 Hz, 1H, H3), 5.23(s, 2H, OCH2).

EXAMPLE 4C,C,C-Trifluoro-N-[5-(3-fluoro-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-methanesulfonamide

To a 50 mL flask charged with 20 mL toluene and 5 mL EtOH was added 250mg (0.54 mmol) of the product from Example 1, 91 mg (0.75 mmol) ofphenylboronic acid, and 3 mL of aqueous 5% potassium carbonate solution.The flask was stirred and degassed for 5 minutes with a steady stream ofnitrogen, after which 35 mg (0.03 mmol) of tetrakis(triphenylphosphine)palladium(0) was added. The mixture was heated to 70° C. for 18 hr underan atmosphere of nitrogen. At the end of this time the solution wasconcentrated and diluted with 30 mL of saturated ammoniun chloridesolution. The mixture was extracted 2× with ethyl acetate and theorganic layers combined and dried (MgSO₄), then concentrated. The crudesolid was chromatographed on silica gel eluting with 30% ethylacetate:hexane. Concentration yielded 0.165 mg (68%) of the titlecompound as a solid. The solid was recrystallized from ethylacetate:hexane to yield 0.13 g of the title product as colorlesscrystals, m.p. 123-125° C.

NMR (400 MHz, DMSO-d6) δ12.15 (bs, 1H, NH), 8.20 (d, J=8 Hz, 1H, H8),7.36-7.54 (m, 12H, ArH), 7.18 (d, J=8 Hz, 1H, ArH), 5.38 (s, 2H, OCH2).

Anal. Calcd. for C24H17F4N1O3S1: C, 60.63; H, 3.60; N, 2.94. Found: C,60.25; H, 3.54; N, 2.88.

EXAMPLE 5C,C,C-Trifluoro-N-[5-(3-fluoro-4′-trifluoromethyl-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-methanesulfonamide

Following the procedure of Example 4, the product of Example 3 andtrifloromethyl benzene boronic acid was converted to the title product,m.p. 98-100° C.

NMR (400 MHz, DMSO-d6) δ12.15 (bs, 1H, NH), 8.18 (d, J=8 Hz, 1H, H8),7.96(d, J=8 Hz, 2H, ArH), 7.82 (d, J=8 Hz, 2H, ArH), 7.58-7.74 (m, 5H,ArH), 7.46(m, 3H, ArH), 7.38 (d, J=8 Hz, 1H, ArH), 7.14(d, J=8 Hz, 1H,H6) 5.41 (s, 2H, OCH2).

Anal. Calcd. for C25H16F7N1O3S1: C, 55.25; H, 2.97; N, 2.58. Found: C,55.12; H, 3.18; N, 2.47.

EXAMPLE 6N-[5-(4′-tert-Butyl-3-fluoro-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-C,C,C-trifluoro-methanesulfonamide

Following the procedure of Example 4, the product of Example 3 and4-t-butyl benzene boronic acid was converted to the title product, m.p.162-164° C.

NMR (400 MHz, DMSO-d6) δ12.18 (bs, 1H, NH), 8.21 (d, J=8 Hz, 1H, H8),7.45-7.78 (m, 8H, ArH), 7.20 (d, J=8 Hz, 1H, ArH), 7.17 (d, J=8 Hz, 1H,H6), 5.41 (s, 2H, OCH2), 1.36 (s, 9H, C(CH3)).

Anal. Calcd. for C28H25F4N1O3S1: C, 63.27; H, 4.74; N, 2.64. Found: C,62.78; H, 4.75; N, 2.53.

EXAMPLE 7N-[5-(3,4′-Difluoro-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-C,C,C-trifluoro-methanesulfonamide

Following the procedure of Example 4, the product of Example 3 and4-fluoro benzene boronic acid was converted to the title product, m.p.134-136° C.

NMR (400 MHz, DMSO-d6) δ12.08 (bs, 1H, NH), 8.19 (d, J=8 Hz, 1H, H8),7.28-7.82 (m, 11H, ArH), 7.17 (d, J=8 Hz, 1H, H6), 5.41 (s, 2H, OCH2).

Anal. Calcd. for C24H16F5N1O3S1: C, 58.42; H, 3.27; N, 2.84. Found: C,58.08; H, 3.28; N, 2.68.

EXAMPLE 8N-[5-(4′-Chloro-3-fluoro-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-C,C,C-trifluoro-methanesulfonamide

Following the procedure of Example 4, the product of Example 3 and4-chloro benzene boronic acid was converted to the title product, m.p.151-153° C.

NMR (400 MHz, DMSO-d6) δ12.08 (bs, 1H, NH), 8.22 (d, J=8 Hz, 1H, H8),7.26-7.78 (m, 10H, ArH), 7.38 (d, J=8 Hz, 1H, ArH), 7.18 (d, J=8 Hz, 1H,H6), 5.41 (s, 2H, OCH2).

Anal. Calcd. for C24H16Cl1F4N1O3S1: C, 56.53; H, 3.16; N, 2.75. Found:C, 56.85; H, 3.15; N, 2.54.

EXAMPLE 9N-[5-(3′,4′-Dichloro-3-fluoro-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-C,C,C-trifluoro-methanesulfonamide

Following the procedure of Example 4, the product of Example 3 and3,4-dichloro benzene boronic acid was converted to the title product,m.p. 172-174° C.

NMR (400 MHz, DMSO-d6) δ12.08 (bs, 1H, NH), 8.17 (d, J=8 Hz, 1H, H8),8.04 (s, 1H, ArH), 7.43-7.78 (m, 8H, ArH), 7.38 (d, J=8 Hz, 1H, ArH),7.16 (d, J=8 Hz, 1H, H6), 5.41 (s, 2H, OCH2).

EXAMPLE 11N-[5-(4-Chloro-4′-fluoro-biphenyl-3-ylmethoxy)-naphthalen-2-yl]-C,C,C-trifluoro-methanesulfonamide

The title compound was prepared from 2-Chloro, (4-fluorphenyl) benzylchloride according to the procedure of Example 1, m.p. 155-157 DMSO: δ12.1(s, 1H), 7.0-8.3(m, 13H, arom), 5.4 (s, 2H). CHN 56.53, 3.16, 2.75.Found 56.13, 3.23, 2.48.

EXAMPLE 12

N-[5-(4′-Fluoro-4′-methoxy-biphenyl-3-ylmethoxy)-naphthalen-2-yl]-C,C,C-trifluoro-methanesulfonamidewas prepared from 2-Fluoro, (4-fluorphenyl) benzyl chloride according tothe procedure of Example 1, m.p. 125-127 DMSO: δ 12.1(s, 1H), 7.0-8.3(m,13H, arom), 5.4 (s, 2H). CHN 59.40, 3.79, 2.77. Found 59.45, 4.37, 3.08.

EXAMPLE 13N-[5-(3′,5′-Dichloro-biphenyl-3-ylmethoxy)-naphthalen-2-yl]-C,C,C-trifluoro-methanesulfonamide

The title compound was prepared from 3-(3,5-dichloro phenyl) benzylchloride according to the procedure of Example 1, m.p. 142-143° C. DMSO:δ 12.1(s, 1H), 7.0-8.3 (m, 13H, arom), 5.4 (s, 2H)DMSO: δ 12.1(s, 1H),7.0-8.3(m, 13H, arom), 5.36 (s, 2H). CHN 54.30, 3.13, 2.64 (0.25 M H₂O).Found 54.08, 2.98, 2.66.

EXAMPLE 14N-[5-(4-naphthalen-2-yl-benzyloxy-3-ylmethoxy)-naphthalen-2-yl]-C,C,C-trifluoro-methanesulfonamide

The title compound was prepared from 4-(2-Naphthyl) benzyl chlorideaccording to the procedure of Example 1, m.p. 142-143° C. DMSO: δ12.1(s, 1H), 7.0-8.3(m, 13H, arom), 5.4 (s, 2H) DMSO: δ 12.1(s, 1H),7.0-8.3(m, 17H, arom), 5.38 (s, 2H). CHN 66.26, 3.97, 2.76. Found 66.96,4.39, 2.92.

EXAMPLE 15 N-[5-(3-fluoro-4′-methoxybiphenyl-4-ylmethoxy)-naphthalen-2-yl]-C,C,C-trifluoro-methanesulfonamide

The title compound was prepared from the product of Example 3 and4-methoxy phenyl boronic acid according to the procedure of Example 2,m.p. 108-11° C. DMSO: δ 12.1(s, 1H), 7.0-8.3(m, 13H, arom), 5.4 (s,2H)DMSO: δ 11.9(s, 1H), 7.0-8.2(m, 13H, arom), 5.36 (s, 2H), 3.8(s, 3H).CHN 57.36, 4.04, 2.68 (1 M H₂O). Found 57.76, 3.55, 2.46.

EXAMPLE 16N-[5-(3′,5′-Dichloro-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-C,C,C-trifluoro-methanesulfonamide

The title compound was prepared from the product of Example 1 and3,5-dichloro phenyl boronic acid according to the procedure of Example2, m.p. 138-140 DMSO: δ 12.1(s, 1H), 7.0-8.3(m, 13H, arom), 5.38 (s,2H). CHN 53.84, 3.20, 2.62 (0.5 M H₂O) Found 53.97, 3.02, 2.40.

EXAMPLE 17N-[5-(4′-Fluoro-biphenyl-3-ylmethoxy)-naphthalen-2-yl]-C,C,C-trifluoro-methanesulfonamide

The title compound was prepared from 3-(4-fluoro phenyl) benzyl chlorideaccording to the procedure of Example 1, m.p. 110-112° C. DMSO: δ12.1(s, 1H), 7.0-8.3(m, 14H, arom), 5.36 (s, 2H). CHN 60.63, 3.60, 2.94.Found 61.03, 3.74, 2.73.

EXAMPLE 18N-[5-(4′-Fluoro-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-C,C,C-trifluoro-methanesulfonamide

The title compound was prepared from the product of Example 1 and4-florophenyl boronic acid according to the procedure of Example 2, m.p.139-140° C. DMSO: δ 12.0 broad (s, 1H), 7.0-8.3(m, 14H, arom), 5.36 (s,2H). CHN 60.63, 3.60, 2.94. Found 60.60, 3.50, 2.83.

EXAMPLE 19N-[5-(Biphenyl-2-ylmethoxy)-naphthalen-2-yl]-C,C,C-trifluoromethanesulfonamidewas prepared from 2-phenyl benzyl chloride

The title compound was prepared according to the procedure of Example 1,m.p. 119-121° C. NMR (400 MHz, DMSO) δ: 8.08 (d, J=9.0 Hz, 1H); 7.28 (m,14H); 5.15 (s, 2H). Anal. Calcd. for C₂₄H₁₈F₃NO₃S: C, 63.01; H, 3.97; N,3.06. Found: C, 63.36; H, 4.25; N, 3.25.

EXAMPLE 20C,C,C-Trifluoro-N-[5-(4′-methoxy-biphenyl-3-ylmethoxy)-naphthalen-2-yl]-methanesulfonamide

The title compound was prepared from 3-(4-methoxyphenyl) benzyl chlorideaccording to the procedure of Example 1, m.p. 123-125.

¹H NMR (400 MHz, DMSO) δ: 8.24 (d, 1H, J=9.0 Hz); 7.39 (m, 13H); 5.36(s, 2H).

Anal. Calcd. for C₂₅H₂₀F₃NO₄S: C, 61.6; H, 4.14; N, 2.87. Found: C,57.48; H, 4.14; N, 2.76; 487.5016 EI m/z 487.

EXAMPLE 21N-[5-(4′-Chloro-4-methoxy-biphenyl-3-ylmethoxy)-naphthalen-2-yl]-C,C,C-trifluoromethanesulfonamide

The title compound was prepared from 2-Methoxy-(5-chlorophenyl) benzylchloride according to the procedure of Example 1, m.p. 155-157° C.

¹H NMR (400 MHz, DMSO) δ: 8.17 (d, J=9.0 Hz, 1H); 7.46 (m, 12H); 5.66(s, 2H); 3.88 (s, 3H).

Anal. Calcd. for C₂₅H₁₉ClF₃NO₄S: C, 57.53; H, 3.67; N, 2.68. Found: C,57.16; H, 3.85; N, 2.51; 521.947 (+)FAB m/z 522 (M+H), 544 (M+Na).

EXAMPLE 22N-[5-(4′-Chloro-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-C,C,C-trifluoromethanesulfonamide

The title compound was prepared from the product of Example 1 and4-chlorophenyl boronic acid according to the procedure of Example 2,m.p. 131-133.

¹H NMR (DMSO) δ: 8.24 (d, J=9.0 Hz, 1H); 7.61 (m, 12H); 7.10 (d, J=7.5Hz, 1H); 5.37 (s, 2H).

Anal. Calcd. for C₂₄H₁₇ClF₃NO₃S: C, 58.6; H, 3.48; N, 2.85. Found: C,56.27; H, 3.46; N, 2.84; 491.9198 EI m/z 491.

EXAMPLE 23C,C,C-Trifluoro-N-[5-(2-methyl-biphenyl-3-ylmethoxy)-naphthalen-2-yl]-methanesulfonamide

The title compound was prepared from 2-Methyl, 3-phenyl benzyl chlorideaccording to the procedure of Example 1, m.p. 124-125° C.

¹H NMR (DMSO) δ: 8.22 (d, J=9.0 Hz, 1H); 7.74 (d, J=2.2 Hz, 1H); 7.37(m, 12H); 5.34 (s, 2H); 2.25 (s, 3H).

Anal. Calcd. for C₂₅H₂₀F₃NO₃S: C, 63.69; H, 4.28; N, 2.97. Found: C,62.91; H, 4.92; N, 2.81.

EXAMPLE 24C,C,C-Trifluoro-N-[5-(4-pyridin-2-yl-benzyloxy)-naphthalen-2-yl]-methanesulfonamide

The title compound was prepared from 4-(2-pyridyl) benzyl chlorideaccording to the procedure of Example 1, m.p.119-120.

¹H NMR (400 MHz, DMSO) δ: 8.01 (m, 11H); 7.08 (d, J=6.8 Hz, 1H); 5.38(s, 2H).

Anal. Calcd. for C₂₃H₁₇F₃N₂O₃S: C, 60.26; H, 3.74; N, 6.11. Found: C,58.66; H, 3.84; N, 5.81; 458.4628 EI m/z 458.

EXAMPLE 25N-[5-(3′-Chloro-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-C,C,C-trifluoromethanesulfonamide

The title compound was prepared from the product of Example 1 and3-chlorophenyl boronic acid according to the procedure of Example 2,m.p. 170-171° C.

¹H NMR (400 MHz, DMSO) δ: 8.26 (d, J=9.0 Hz, 1H); 7.58 (m, 12H); 7.09(d, 1H, J=6.6 Hz); 5.34 (s, 2H).

Anal. Calcd. for C₂₄H₁₇ClF₃N₂O₃S: C, 58.60; H, 3.48; N, 5.69. Found: C,57.95; H, 3.30; N, 2.63; 491.9152 (−)ESI m/z 490 (M−H).

EXAMPLE 26C,C,C-Trifluoro-N-[5-(6-fluoro-4′-methoxy-biphenyl-3-ylmethoxy)-naphthalen-2-yl]-methanesulfonamide

The title compound was prepared from 4-Fluoro, 5-(4-methoxy phenyl)benzyl chloride according to the procedure of Example 1, m.p. 132-133°C.

¹H NMR (400 MHz, DMSO) δ: 8.22 (d, J=9.0 Hz, 1H); 7.39 (m, 12H); 5.34(s, 2H); 3.81 (s, 3H).

Anal. Calcd. for C₂₅H₁₉F₄NO₄S: C, 59.03; H, 3.78; N, 2.75. Found: C,58.50; H, 3.88; N, 3.02; 505.4865 (+)ESI m/z 523 (M+NH4).

EXAMPLE 27C,C,C-Trifluoro-N-[5-biphenyl-3-ylmethoxy)-naphthalen-2-yl]-methanesulfonamide

The title compound was prepared from 4-phenyl benzyl chloride accordingto the procedure of Example 1, m.p. 122-125° C.

Anal. Calcd. for C₂₄H₁₈F₃NO₃S: C, 63.01; H, 3.97; N, 3.06. Found: C,63.19; H, 4.01; N, 2.92.

NMR (400 MHz, DMSO) δ: 8.25 (d, J=9 Hz, 1H, ArH), 7.62-7.74 (m, 7H,ArH), 7.34-7.51 (M, 6H, ArH), 7.02 (d, J=7 Hz, 1H, H2), 5.36 (s, 2H,OCH2).

EXAMPLE 28C,C,C-Trifluoro-N-[5-(2-chloro,4-bromophen-2-yl-methoxy)-naphthalen-2-yl]-methanesulfonamide

Step 1. Preparation of5-(2-chloro,4-bromophen-2-yl-methoxy)-naphthalen-2-yl-amine

To a solution of 0.30 g (12.5 mmol) of 95% sodium hydride and 1 drop of15-crown-5 in 150 mL of THF was added dropwise a solution of 1.59 g (10mmol) of 6-amino-1-naphthol at 0° C. After stirring for 0.5 hr 3.1 g (13mmol) of 4-bromo,2-chloro benzyl chloride was added in one portion. Themixture was stirred at room temperature for 5 hr. At the end of thistime, the solution was concentrated and the residue washed with 10 ml ofsaturated ammonium chloride and extracted 2 times with 40 mL of ethylacetate. The organic layers were combined, dried (MgSO₄) andconcentrated. The crude solid was chromatographed on silica gel elutingwith 40% ethyl acetate:hexane. Concentration yielded 2.3 g (64%) of theproduct as a brown solid, used in the next step without furtherpurification

Step 2 Preparation of the Title Compound

To a 100 mL flask charged with 50 mL of methylene chloride is added 0.30mL (2.0 mmol) of triethyl amine and 0.63 g (1.72 mmol) of the productfrom Step 1. The flask was cooled to −20° C. where upon a solution of0.32 mL (1.82 mmol) of trifluoromathane sulfonic anhydride in 10 mL ofmethylene chloride was added dropwise under nitrogen atmosphere. After ½hr, 1 mL of a 1M solution tetra n-butyl ammonium flouride was added andthe mixture stirred for 16 hr. At the end of this time, the solution wasconcentrated, diluted with 20 mL of saturated ammonium chloride andextracted 2 times with ethyl acetate. The organic layers were combined,dried (MgSO₄) and concentrated. The crude solid was chromatographed onsilica gel eluting with 30% ethyl acetate:hexane. Concentration yielded1.8 g (68%) of the title compound as a brown solid.

NMR (200 MHz, CDCl3) δ 11.80 (bs, 1H, NH), 8.32 (d, J=8 Hz, 1H, H8),7.63 (s, 1H, H1), 7.23-7.53 (m, 6H, ArH), 6.73 (d, J=8 Hz, 1H, H3), 5.23(s, 2H, OCH2).

EXAMPLE 29N-[5-(3-Chloro-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-C,C,C-trifluoro-methanesulfonamide

To a 50 mL flask charged with 20 mL toluene and 5 mL EtOH was added 250mg (0.51 mmol) of the product from Example 28, 91 mg (0.75 mmol) ofphenylboronic acid, and 3 mL of aqueous 5% potassium carbonate solution.The flask was stirred and degassed for 5 minutes with a steady stream ofnitrogen, after which 35 mg (0.03 mmol) of tetrakis(triphenylphosphine)palladium(0) was added. The mixture was heated to 70° C. for 18 hr underan atmosphere of nitrogen. At the end of this time the solution wasconcentrated and diluted with 30 mL of saturated ammoniun chloridesolution. The mixture was extracted 2× with ethyl acetate and theorganic layers combined and dried (MgSO₄), then concentrated. The crudesolid was chromatographed on silica gel eluting with 30% ethylacetate:hexane. Concentration yielded 0.165 mg (68%) of the titlecompound as a solid. The solid was recrystallized from ethylacetate:hexane to yield 0.12 g of the title product as colorlesscrystals, m.p. 131-134° C.

NMR (400 MHz, DMSO-d6) δ12.15 (bs, 1H, NH), 8.22 (d, J=8 Hz, 1H, H8),7.37-7.84 (m, 12H, ArH), 7.16 (d, J=8 Hz, 1H, ArH), 5.42 (s, 2H, OCH2).

Anal. Calcd. for C24H17Cl1F3N1O3S1: C, 57.60; H, 3.480; N, 2.85. Found:C, 57.72; H, 3.41; N, 2.69.

EXAMPLE 30C,C,C-Trifluoro-N-[5-(3,3′,4′-trichloro-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-methanesulfonamide

The title compound was prepared from the product of Example 28 and3,4-dichlorophenyl boronic acid according to the procedure of Example29, m.p. 169-170° C.

NMR (400 MHz, DMSO-d6) δ12.15 (bs, 1H, NH), 8.23 (d, J=8 Hz, 1H, H8),8.04 (d, J=2 Hz, 1H, ArH), 7.93 (d, J=2 Hz, 1H, ArH), 7.71-7.82 (m, 4H,ArH), 7.43-7.56 (m, 3H, ArH), 7.40 (d, J=8 Hz, 1H, ArH), 7.17 (d, J=8Hz, 1H, H6), 5.42 (s, 2H, OCH2).

Anal. Calcd. for C₂₄H₁₅Cl3F3N1O3S1: C, 51.40; H, 2.70; N, 2.50. Found:C, 51.26; H, 2.83; N, 2.51.

EXAMPLE 31N-[5-(3,4′-Dichloro-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-C,C,C-trifluoro-methanesulfonamide

The title compound was prepared from the product of Example 28 and4-chlorophenyl boronic acid according to the procedure of Example 29m.p. 176-178° C.

NMR (400 MHz, DMSO-d6) δ12.15 (bs, 1H, NH), 8.23 (d, J=8 Hz, 1H, H8),7.88 (s, 1H, ArH), 7.71-7.84 (m, 5H, ArH), 7.43-7.58 (m, 4H, ArH), 7.40(d, J=8 Hz, 1H, ArH), 7.16 (d, J=8 Hz, 1H, H6), 5.42 (s, 2H, OCH2).

Anal. Calcd. for C24H16Cl2F3N1O3S1: C, 54.76; H, 3.06; N, 2.66. Found:C, 54.65; H, 2.96; N, 2.60.

EXAMPLE 32N-[5-(4-Cyclohexyl-benzyloxy)-naphthalen-2-yl}-C,C,C-trifluoro-methanesulfonamide

The title compound was prepared from 4-cyclohexyl benzyl chlorideaccording to the procedure of Example 1, m.p. 108-110° C. DMSO: δ 12.1(s, 1H), 7.0-8.2(m, 10H, arom), 5.25 (s, 2H), 1.1-1.8(m, 11H). NMR62.19, 5.22, 3.02. Found 62.19, 5.30, 2.96.

EXAMPLE 33N-[5-(4-Tert-butyl-benzyloxy)-naphthalen-2-yl}-C,C,C-trifluoro-methanesulfonamide

The title compound was prepared from 4-t-butyl benzyl chloride accordingto the procedure of Example 1, oil, NMR: DMSO: δ 12.1 (s, 1H),7.0-8.2(m, 10H, arom), 5.25 (s, 2H), 1.3(s, 9H). CHN 60.40, 5.07, 3.20.Found 60,46, 5.24, 2.84.

EXAMPLE 34N-[5-(2,4-Dichloro-benzyloxy)-naphthalen-2-yl}-C,C,C-trifluoro-methanesulfonamide

The title compound was prepared from 2,4-dichloro benzyl chlorideaccording to the procedure of Example 1, m.p. 142-144° C. DMSO: δ 12.1(s, 1H), 7.0-8.2(m, 9H, arom), 5.32 (s, 2H). CHN 48.02, 2.69, 3.11.Found 47.46, 2.77, 2.90.

EXAMPLE 35N-[5-(3-Chloro-4-methoxy-benzyloxy)-naphthalen-2-yl}-C,C,C-trifluoro-methanesulfonamide

The title compound was prepared from 3-chloro benzyl chloride accordingto the procedure of Example 1, m.p. 129-130° C. DMSO: δ 12.1 (s, 1H),7.0-8.2(m, 9H, arom), 5.25 (s, 2H), 3.85 (s, 3H). CHN 51.55, 3.58, 2.88.Found 51.19, 3.39, 3.14.

EXAMPLE 36N-[5-(4-Bromo-2-fluoro-benzyloxy)-naphthalen-2-yl}-C,C,C-trifluoromethanesulfonamide

The title compound was prepared from 4-Bromo,2-fluoro benzyl bromideaccording to the procedure of Example 1, m.p. 123-125° C. DMSO: δ 12.1(s, 1H), 7.0-8.2(m, 9H, arom), 5.3 (s, 2H). CHN 45.20, 2.53, 2.93. Found45.05, 2.54, 2.74.

EXAMPLE 37N-[5-(4-Benzyloxy-benzyloxy)-naphthalen-2-yl}-C,C,C-trifluoromethanesulfonamide

The title compound was prepared from 4-benzyloxy benzyl chlorideaccording to the procedure of Example 1, oil, DMSO: δ 12.1 (s, 1H),6.9-8.2(m, 15H, arom), 5.25 (s, 2H), 5.15 (s, 2H), CHN 61.60, 4.14,2.87. Found 61.21, 4.09, 2.82.

EXAMPLE 38N-[5-(3-Bromo-benzyloxy)-naphthalen-2-yl}-C,C,C-trifluoromethanesulfonamide

The title compound was prepared from 3-Bromo benzyl bromide according tothe procedure of Example 1, m.p. 113-115° C. DMSO: δ 12.1 (s, 1H),7.0-8.3(m, 10H, arom), 5.3 (s, 2H) NMR 46.97, 2.85, 3.04. Found 47.12,3.01, 3.00.

EXAMPLE 39N-[5-(2,6-Dichloro-pyridin-4-yl)-naphthalen-2-yl]-C,C,C-trifluoromethanesulfonamide

The title compound was prepared from 2,6-Dichloro benzyl chlorideaccording to the procedure of Example 1 m.p. 185-187° C. CDCl₃: δ 7.0(s, 1H), 6.7-8.4(m, 8H, arom), 5.25 (s, 2H). CHN 45.25, 2.46, 6.21.Found 44.87, 2.66, 5.99.

EXAMPLE 40N-[5-(4-Trifluoromethoxy-benzyloxy)-naphthalen-2-yl}-C,C,C-trifluoromethanesulfonamide

The title compound was prepared from 4-Trifluoromethyl benzyl chlorideaccording to the procedure of Example 1, m.p. 80-82° C. DMSO: δ 12.1 (s,1H), 7.0-8.3(m, 10H, arom), 5.35 (s, 2H). CHN 49.04, 2.82, 3.01. Found49.55, 2.93, 2.92.

EXAMPLE 41N-[5-(4-Iodo-benzyloxy)-naphthalen-2-yl}-C,C,C-trifluoromethanesulfonamide

The title compound was prepared from 4-Bromo,2-fluoro benzyl bromideaccording to the procedure of Example 1 was prepared from 4-Iodo benzylbromide according to the procedure of Example 1, m.p. 120-122° C. DMSO:δ 12.1 (s, 1H), 7.0-8.3(m, 10H, arom), 5.28 (s, 2H). CHN 42.62, 2.58,2.76. Found 44.83, 3.23, 2.39.

EXAMPLE 42C,C,C-Trifluoro-N-{5-[6-(4-fluoro-phenyl)-pyridin-2-ylmethoxy]-naphthalen-2-yl}-methanesulfonamide

Step 1. Preparation of 2-methyl, 6-trifluoromethanesulfonyl pyridine

To a flask charged with 2.18 g (20 mmol) of 6-hydroxy, 2-methyl pyridineand 3.06 ml (22 mmol) of triethyl amine dissolved in 200 mL of methylenechloride was added dropwise a solution of of 3.70 ml (22 mmol) oftrifluoromethane sulfonic anhydride in 50 mL of methylene chloride at 0°C. After 2 h, the solution was concentrated, and the residue washed withwater and extracted twice with 100 mL of ethyl acetate. After upondrying and concentrating, the dark oil was subjected to flashchromatography on silica gel. Elution with 20% ethyl acetate:hexaneyielded a light yellow oil used immediately in subsequent steps withoutfurther purification.

Step 2. Preparation of 2-methyl, 6-(4-fluorophenyl) pyridine.

2.8 g (10.8 mmol) of the product obtained from step 1, 1.4 g (8.92 mmol)of 4-fluorobenzene boronic acid and 2.84 g (13.4 mmol) of potassiumphosphate were placed in a flask along with 80 mL of dioxane. Thesolution was degassed with nitrogen, whereupon 85 mg oftetrakis(triphenylphosphine) palladium was added. The solution washeated to 70° C. for 24 hr. At the end of this time, the solution wasconcentrated, and the residue washed with water and extracted with ethylacetate (2×50 mL). The combined extracts were dried and concentratedthen the residue chromatographed over silica gel. Elution with 20% ethylacetate:hexane yielded 1.8 g (89%) of a light yellow oil.

NMR (200 MHz, CDCl3) δ 7.96 (m, 2H, ArH), 7.64 (t, J=8 Hz, 1H, ArH),7.45 (d, J=8 Hz, 1H, ArH), 7.16 (m, 3H, ArH), 2.63 (s, 3H, CH3).

Step 3. Preparation of 2-chloromethyl, 6-(4-fluorophenyl) pyridine

0.60 g (3.2 mmol) of the product of step 2 was dissolved in 50 mL ofcarbon tetrachloride, along with 0.54 g (3.5 mmol) of N-chlorosuccinimide and a catalytic amount of benzoyl peroxide. After refluxingfor 20 hr, the solution was concentrated and filtered through a plug ofsilica gel eluting with 20% ethyl acetate:hexane. The resulting oil wascontaminated with ˜10% of unreacted starting material and was used inthe next step without further purification.

NMR (200 MHz, CDCl3) δ 7.96 (m, 2H, ArH), 7.63 (m, 1H, ArH), 7.43 (m,1H, ArH), 7.17 (m, 3H, ArH), 4.72 (s, 2H, CH2Cl).

Step 4. Preparation of the Title Compound

The product from step 3 was converted to the title compound followingthe procedure of Example 1 (yield 42%), m.p. 173-174° C.

NMR (400 MHz, DMSO-d6) δ12.05 (bs, 1H, NH), 8.35 (d, J=8 Hz, 1H, ArH),8.18 (m, 2H, ArH), 7.94 (m, 2H, ArH), 7.73(s, 1H, ArH), 7.62 (d, J=8 Hz,1H, ArH), 7.30-7.55 (m, 5H, ArH), 7.18 (s, 1H, ArH), 5.44 (s, 2H, OCH2).

Anal. Calcd. for C23H16F4N2O3S1: C, 57.98; H, 3.38; N,5.88. Found: C,58.23; H, 3.37; N, 5.82.

EXAMPLE 43C,C,C-Trifluoro-N-{5-[6-(4-trifluoromethyl-phenyl)-pyridin-2-ylmethoxy]-naphthalen-2-yl}-methanesulfonamide

The title compound was prepared according to the procedure of example42, except that trifluoromethyl benzeneboronic acid was used in step 2in place of 4-fluoro benzeneboronic acid, m.p. 180-182° C.

NMR (400 MHz, DMSO-d6) δ12.05 (bs, 1H, NH), 8.35 (m, 3H, ArH), 8.08 (m,2H, ArH), 7.84 (d, J=8 Hz, 2H, ArH), 7.75(s, 1H, ArH), 7.62 (d, J=8 Hz,1H, ArH), 7.41-7.55 (m, 3H, ArH), 7.18 (s, 1H, ArH), 5.44 (s, 2H, OCH2).

Anal. Calcd. for C24H16F6N2O3S1: C, 54.76; H, 3.06; N,5.32. Found: C,54.80; H, 3.30; N, 5.15.

EXAMPLE 44N-{5-[2-(4-Chloro-phenyl)-thiazol-4-ylmethoxy]-naphthalen-2-yl}-C,C,C-trifluoro-methanesulfonamide

The title compound was prepared from 4-chloromethyl-2-(4-chloro) phenylthiazole following the procedure of Example 1 m.p. 151-153° C.

NMR (400 MHz, DMSO-d6) δ 12.10 (bs, 1H, NH), 8.25 (d, J=8 Hz, 1H ArH),7.96 (m, 3H, ArH), 7.75 (s, 1H, N═CH—S), 7.42-7.57 (m, 4H, ArH), 7.38(d, J=8 Hz, 1H, ArH), 7.18 (d, 1H, H6), 5.42 (s, 2H, OCH2).

Anal. Calcd. for C21H14Cl1F3N2O3S2: C, 50.56; H, 2.83; N, 5.62. Found:C, 50.41; H, 3.44; N, 5.31.

EXAMPLE 45C,C,C-Trifluoro-N-{5-[2-(4-fluoro-phenyl)-thiazol-4-ylmethoxy]-naphthalen-2-yl}-methanesulfonamide

The title compound was prepared from 4-chloromethyl-2-(4-fluoro phenyl)thiazole following the procedure of Example 1 m.p. 170-173° C.

NMR (400 MHz, DMSO-d6) δ 12.10 (bs, 1H, NH), 8.25 (d, J=8 Hz, 1H ArH),8.12 (m, 2H, ArH), 7.92(s, 1H, ArH), 7.75 (s, 1H, N═CH—S), 7.31-7.57 (m,5H, ArH), 7.18 (d, 1H, H6), 5.42 (s, 2H, OCH2).

Anal. Calcd. for C21H14F4N2O3S2: C, 52.28; H, 2.92; N, 5.81. Found: C,52.36; H, 2.77; N, 5.51.

EXAMPLE 46N-{5-[2-(2,4-Difluoro-phenyl)-thiazol-4-ylmethoxy]-naphthalen-2-yl}-C,C,C-trifluoro-methanesulfonamide

The title compound was prepared from 4-chloromethyl-2-(2,4-difluorophenyl) thiazole following the procedure of Example 1, m.p. 191-192° C.

NMR (400 MHz, DMSO-d6) δ 12.10 (bs, 1H, NH), 8.24 (m, 2H, ArH), 8.14 (s,1H, ArH), 7.92(s, 1H, ArH), 7.75 (s, 1H, N═CH—S), 7.41-7.57 (m, 3H,ArH), 7.38 (d, J=8 Hz, 1H, ArH), 7.31 (t, J=8 Hz, 1H, ArH), 7.18 (d, 1H,H6), 5.42 (s, 2H, OCH2).

Anal. Calcd. for C21H13F5N2O3S2: C, 50.4; H, 2.62; N, 5.60. Found: C,50.16; H, 2.69; N, 5.35.

EXAMPLE 47N-{5-[2-(4-tert-Butyl-phenyl)-thiazol-4-ylmethoxy]-naphthalen-2-yl}-C,C,C-trifluoro-methanesulfonamide

The title compound was prepared from 4-chloromethyl-2-(4-t-butyl phenyl)thiazole following the procedure of Example 1, m.p. 174-175° C.

NMR (400 MHz, DMSO-d6) δ 12.10 (bs, 1H, NH), 8.25 (d, J=8 Hz, 1H, ArH),7.85 (m, 3H, ArH), 7.77 (s, 1H, N═CH—S), 7.45-7.57 (m, 4H, ArH), 7.38(d, J=8 Hz, 1H, ArH), 7.18 (d, J=8 Hz, 1H, H6), 5.42 (s, 2H, OCH2), 1.24(s, 9H, C(CH3)3).

Anal. Calcd. for C25H23F3N2O3S2: C, 57.68; H, 4.45; N, 5.38. Found: C,58.16; H, 4.71; N, 5.01.

EXAMPLE 48N-{5-[2-(3-Chloro-4-fluoro-phenyl)-thiazol-4-ylmethoxy]-naphthalen-2-yl}-C,C,C-trifluoro-methanesulfonamide

The title compound was prepared from 4-chloromethyl-2-(3-chloro,4-fluorophenyl) thiazole following the procedure of Example 1 m.p. 169-170° C.

NMR (400 MHz, DMSO-d6) δ 12.10 (bs, 1H, NH), 8.23 (d, J=8 Hz, 1H, ArH),8.17(d, J=8 Hz, 1H, ArH), 7.98 (m, 2H, ArH), 7.77 (s, 1H, N═CH—S),7.45-7.57 (m, 3H, ArH), 7.38 (d, J=8 Hz, 1H, ArH), 7.18 (d, J=8 Hz, 1H,H6), 5.42 (s, 2H, OCH2).

Anal. Calcd. for C21H13F4N2O3S2: C, 48.80; H, 2.54; N, 5.42. Found: C,48.95; H, 2.82; N, 5.12.

EXAMPLE 49

N-{5-[2-(6-Chloro-pyridin-3-yl)-thiazol-4-ylmethoxy]-naphthalen-2-yl}-C,C,C-trifluoro-methanesulfonamide

The title compound was prepared from4-chloromethyl-2-(6-chloro-pyridin-3-yl) thiazole following theprocedure of Example 1, m.p. 154-156° C.

NMR (400 MHz, DMSO-d6) δ 12.10 (bs, 1H, NH), 9.01(s, 1H, ArH), 8.39 (d,J=8 Hz, 1H, ArH), 8.26 (d, J=8 Hz, 1H, ArH), 8.17(d, J=8 Hz, 1H, ArH),7.78 (s, 1H, N═CH—S), 7.45-7.57 (m, 2H, ArH), 7.40 (d, J=8 Hz, 1H, ArH),7.18 (d, J=8 Hz, 1H, H6), 5.42 (s, 2H, OCH2).

Anal. Calcd. for C21H13F4N2O3S2: C, 48.05; H, 2.62; N, 8.41. Found: C,47.86; H, 3.09; N, 8.28.

EXAMPLE 50N-{5-[2-(2,3-Dihydro-benzo[1,4]dioxin-2-yl)-thiazol-4-ylmethoxy]-naphthalen-2-yl}-C,C,C-trifluoro-methanesulfonamide

The title compound was prepared from4-chloromethyl-2-(2,3-dihydro-benzo[1,4]dioxin-2-yl) thiazole followingthe procedure of Example 1, m.p. 183-185° C.

NMR (400 MHz, DMSO-d6) δ 12.10 (bs, 1H, NH), 8.23 (d, J=8 Hz, 1H, ArH),7.93 (s, 1H, ArH), 7.76 (s, 1H, ArH), 7.43-7.58 (m, 3H, ArH), 7.18 (d,J=8 Hz, 1H, N═CH—S), 7.03 (m, 1H, ArH), 6.91 (m, 3H, ArH), 5.79 (m, 1H,OCH), 5.39 (s, 2H, OCH2), 4.38-4.59 (m, 2H, OCH2).

Anal. Calcd. for C23H17F3N2O5S2: C, 52.87; H, 3.28; N, 5.36. Found: C,52.55; H, 2.98; N, 5.25.

EXAMPLE 51C,C,C-Trifluoro-N-[5-(2-phenyl-thiazol-4-ylmethoxy)-naphthalen-2-yl]-methanesulfonamide

The title compound was prepared from 4-chloromethyl-2-phenyl thiazolefollowing the procedure of Example 1, m.p. 89-99° C.

¹H NMR (400 MHz, DMSO) δ: 8.26 (d, J=9.2 Hz, 1H); 7.57 (m, 11H); 5.43(s, 2H).

Anal. Calcd. for C₂₁H₁₅F₃N₂O₃S₂: C, 54.84; H, 3.49; N, 5.92. Found: C,54.69; H, 3.68; N, 5.71; 464.4883 EI m/z 464.

EXAMPLE 52C,C,C-Trifluoro-N-{5-[2-(5-trifluoromethyl-pyridin-2-yl)-thiazol-4-yl-methoxy]naphthalen-2-yl}-methanesulfonamide

The title compound was prepared from4-chloromethyl-2-(5-trifluoromethyl-pyridin-2-yl) thiazole following theprocedure of Example 1, m.p. 197-198° C.

¹H NMR (400 MHz, DMSO) δ: 9.06 (s, 1H); 8.30 (m, 3H); 8.15 (s 1H); 7.73(d, J=2.2 Hz, 1H); 7.45 (m, 3H); 7.18 (d, J=7.2 Hz, 1H); 5.48 (s, 2H).

Anal. Calcd. for C₂₁H₁₃F₈N₃O₃S₂: C, 47.28; H, 2.46; N, 7.78. Found: C,47.31; H, 2.68; N, 7.72; 533.474 EI m/z 533.

EXAMPLE 53C,C,C-Trifluoro-N-{5-[2-(4-methoxy-phenyl)-thiazol-4-ylmethoxy]-naphthalen-2-yl}-methanesulfonamide

The title compound was prepared from 4-chloromethyl-2-(4-methoxy-phenyl)thiazole following the procedure of Example 1 m.p. 151-152° C.

¹H NMR (400 MHz, DMSO) δ: 8.26 (d, J=9.0 Hz, 1H); 7.47 (m, 10H); 5.84(s, 2H); 3.82 (s, 3H).

Anal. Calcd. for C₂₂H₁₇F₃N₂O₄S₂: C, 54.41; H, 4.00; N, 5.35. Found: C,53.97; H, 4.06; N, 5.03; 494.5156 EI m/z 494.

EXAMPLE 54N-{5-[2-(2-Chloro-phenyl)-thiazol-4-ylmethoxy]-naphthalen-2-yl}-C,C,C-trifluoromethanesulfonamide

The title compound was prepared from 4-chloromethyl-2-(2-chloro-phenyl)thiazole following the procedure of Example 1, m.p. 128-129° C.

¹H NMR (400 MHz, DMSO) δ: 8.26 (d, J=9.0 Hz, 1H); 7.70 (m, 10H); 5.47(s, 2H).

Anal. Calcd. for C₂₁H₁₄ClF ³ NO₃S₂: C, 50.55; H, 2.83; N, 2.81. Found:C, 49.69; H, 2.70; N, 5.22; 498.9324 (−)ESI m/z 497 (M−H).

EXAMPLE 55C,C,C-Trifluoro-N-{5-[2-(4-trifluoromethoxy-phenyl)-thiazol-4-yl-methoxy]-naphthalen-2-yl}-methanesulfonamide

The title compound was prepared from4-chloromethyl-2-(4-trifluoromethoxyphenyl) thiazole following theprocedure of Example 1, m.p. 131-132° C.

¹H NMR (400 MHz, DMSO) δ: 8.26 (d, J=9.0 Hz, 1H); 8.09 (ddd, J₁=11.9 Hz,J₂=5.1 Hz, J₃=2.9 Hz, 2H); 7.97 (s, 1H); 7.73 (d, J=2.2 Hz, 1H); 7.45(m, 5H); 7.17 (d, J=6.8 Hz, 1H); 5.43 (s, 2H).

Anal. Calcd. for C₂₂H₁₄F₆N₂O₄S₂: C, 48.18; H, 2.57; N, 5.11. Found: C,48.24; H, 2.81; N, 4.82; 548.483 EI m/z 548.

EXAMPLE 56N-{5-[5-Bromo-2-(4-fluoro-phenyl)-thiazol-4-ylmethoxy]-naphthalen-2-yl}-C,C,C-trifluoromethanesulfonamide

The title compound was prepared from 4-chloromethyl-2-(4-fluorophenyl)thiazole following the procedure of Example 1, m.p. 139-140° C.

¹H NMR (400 MHz, DMSO) δ: 8.13 (d, J=9.2 Hz, 1H); 7.67 (m, 8H); 7.19 (d,J=7.2 Hz, 1H); 5.35 (s, 2H).

Anal. Calcd. for C₂₁H₁₃BrF₄N₂O₃S₂: C, 43.38; H, 2.34; N, 4.74. Found: C,43.51; H, 2.22; N, 4.66; 561.3755 (−)ESI m/z 559 (M−H).

EXAMPLE 57N-{5-[2-(4-trufluoromethyl-phenyl)-thiazol-4-ylmethoxy]-naphthalen-2-yl}-C,C,C-trifluoro-methanesulfonamide

The title compound was prepared from4-chloromethyl-2-(4-trifluoromethylphenyl) thiazole following theprocedure of Example 1, m.p. 155-157° C.

¹H NMR (DMSO-d₆, 400 MHz) δ: 8.39 (d, J=8 Hz, 1H, ArH); 8.17 (d, J=8 Hz,2H, ArH); 7.73 (m, 3H, ArH); 7.46 (m, 3H, ArH); 7.35 (d, J=8 Hz, 1H,ArH); 6.97 (m, 2H, ArH and NH); 5.43 (s, 2H, OCH2).

Anal. Calcd. for C22H14F6N2O3S2: C, 49.63; H, 2.65; N, 5.26. Found: C,49.98; H, 3.01; N, 4.66.

EXAMPLE 58N-{5-[5-(4-trifluoromethyl-phenyl)-[1,2,4]-oxadiazol-5-ylmethoxy)-naphthalen-2-yl}-C,C,C-trifluoro-methanesulfonamide

General procedure for preparation of 3-chloromethyl-[1,2,4] oxadiazoles

Step 1. To a solution of 13.8 g of hydroxylamine hydrochloride in 30 mLof water was added 10.6 g of sodium carbonate. The mixture was stirreduntil everything was dissolved. Then 15 mL of chloroacetonitrile wasadded dropwise over a 15 min period (with exterior cooling). Stirred 1 hand then worked up by extracting twice with ether. Concentrated to give10.8 g of chloroacetamide oxime. Used without further purification onsubsequent step.

Step 2. To a solution of 3.0 g (27.6 mmol) of chloroacetamide oxime in50 mL of dry dichloromethane at 0° C. was added 4.6 mL (33.1 mmol) oftriethylamine followed by the dropwise addition of 4.52 mL (30.4 mmol)of 4-trifluoromethylbenzoyl chloride. Monitored via TLC for completereaction (˜2 h). Worked up by pouring into water and extracting withethyl acetate several times. The combined organic layers were washedwith 2 N hydrochloric acid, saturated sodium bicarbonate, and brine.Dried over anhydrous sodium sulfate, decanted, and concentrated in vacuoto give a thick residue. Residue was dissolved in 100 mL of toluene andrefluxed, removing water via a Dean-Stark trap. After reaction wascomplete, the solvent was removed in vacuo to give an orange residue.Flash chomatography of the residue on a silica column eluting with 5-20%ethyl acetate hexane, gave after concentration, 4.5 g (62%) of pure3-chloromethyl-5-(4-trifluoromethylphenyl)-1,2,4-oxadiazole.

Following the General Procedures of Example 1, the product from step 2above was converted to the title product NMR(DMSO-d₆, 400 MHz) δ 12.2(s, 1H), 7.1-8.4(m, 10H, arom), 5.6 (s, 2H).

The following compounds were synthesized from their corresponding acidchlorides according to the above procedure of Example 56:

EXAMPLE 59 N-{5-[5-(4-tert-Butyl-phenyl)-[1,2,4]-oxadiazol-5-ylmethoxy)-naphthalen-2-yl}-C,C,C-trifluoro-methanesulfonamide

The title compound was prepared from 4-t-butyl benzoyl chloride, m.p.154-155 NMR (DMSO-d₆, 400 MHz) δ 12.1 (s, 1H), 7.1-8.3 (m, 10H, arom),5.54 (s, 2H), 1.3(s, 9H). CHN 54.43, 3.48, 9.07. Found 54.13, 3.48,8.75.

EXAMPLE 60N-[5-(5-Adamantan-1-yl-[1,2,4]oxadiazol-3-ylmethoxy)-naphthalen-2-yl]-C,C,C-trifluoro-methanesulfonamide

The title compound was prepared from adamantoyl chloride, m.p. 60-62 NMR(DMSO-d₆, 400 MHz) δ 8.9(s, 1H), 6.9-8.1(m, 6H, arom), 5.4 (s, 2H),3.7(t, 2H), 1.7-2.1 (m, 15H) CHN 56.80, 4.77, 8.28 (BU₄N). Found 59.46,6.00, 7.89.

EXAMPLE 61N-{5-[5-(4-cyano-phenyl)-[1,2,4]-oxadiazol-5-ylmethoxy)-naphthalen-2-yl}-C,C,C-trifluoro-methanesulfonamide

The title compound was prepared from 4-cyano benzoyl chloride, m.p.184-185° C. NMR (DMSO-d₆, 400 MHz) δ 12.1 (s, 1H), 7.1-8.4(m, 10H,arom), 5.6 (s, 2H). CHN 49.41, 3.36, 10.98 (2 M H₂O). Found 49.72, 2.65,10.43.

EXAMPLE 62N-{5-[5-(3-methoxy-phenyl)-[1,2,4]-oxadiazol-5-ylmethoxy)-naphthalen-2-yl}-C,C,C-trifluoro-methanesulfonamide

The title compound was prepared from 3-methoxy benzoyl chloride, m.p.138-140° C. NMR (DMSO-d₆400 MHz) δ 12.1 (s, 1H), 7.1-8.3(m, 10H, arom),5.56 (s, 2H), 3.85(s, 3H). CHN 52.61, 3.36, 8.77. Found 52.44, 3.34,8.70.

EXAMPLE 63N-{5-[5-(3-trifluoromethyl-phenyl)-[1,2,4]-oxadiazol-5-ylmethoxy)-naphthalen-2-yl}-C,C,C-trifluoro-methanesulfonamide

The title compound was prepared from 3-trifluoromethyl benzoyl chloride,m.p. 107-108° C. NMR (DMSO-d₆, 400 MHz) δ 12.2 (s, 1H), 7.1-8.5(m, 10H,arom), 5.6 (s, 2H) CHN 48.75, 2.53, 8.12. Found 48.46, 2.71, 7.90.

EXAMPLE 64N-{5-[5-(4-methoxy-phenyl)-[1,2,4]-oxadiazol-5-ylmethoxy)-naphthalen-2-yl}-C,C,C-trifluoro-methanesulfonamide

The title compound was prepared from 4-t-methoxy benzoyl chloride, m.p.146-148° C. NMR (DMSO-d₆, 400 MHz) δ 12.1 (s, 1H), 7.1-8.3(m, 10H,arom), 5.53 (s, 2H), 3.85 (s, 3H) CHN 52.61, 3.36, 8.77. Found 52.33,3.60, 8.34.

EXAMPLE 65C,C,C-Trifluoro-N-{5-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl-methoxy]-naphthalen-2-yl}-methanesulfonamide

The title compound was prepared from 4-fluoro benzoyl chloride, m.p.131-132° C. NMR (DMSO-d₆, 400 MHz) δ: 8.24 (d, J=9.0 Hz, 1H); 7.74 (m,8H); 7.13 (d, J=7.5 Hz, 1H); 5.81 (s, 2H) Anal. Calcd. forC₂₀H₁₃F₄N₃O₄S: C, 51.40; H, 2.80; N, 8.99. Found: C, 50.75; H, 3.09; N,8.53.

EXAMPLE 66C,C,C-Trifluoro-N-{5-[3-(3-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-5-ylmethoxy]-naphthalen-2-yl}-methanesulfonamide

The title compound was prepared from 3-trifluoro benzoyl chloride m.p.155-156° C. NMR (DMSO-d₆, 400 MHz) δ: 8.32 (d, J=7.9 Hz, 1H); 7.86 (m,8H); 7.15 (d, J=7.7 Hz, 1H); 5.84 (s, 2H).

Anal. Calcd. for C₂₀H₁₃F₄N₃O₄S: C, 48.75; H, 2.53; N, 8.12. Found: C,48.56; H, 2.54; N, 7.99; (+)FAB m/z 518 (M+H).

EXAMPLE 67N-5-(3-thiophen-2-yl)-[1,2,4]oxadiazol-5-ylmethoxy)-naphthalen-2-yl}-C,C,C-trifluoro-methanesulfonamide

The title compound was prepared from 2-thiopheneacetyl chloride m.p.157-159° C. DMSO: δ 12.0 (s, 1H), 7.0-8.3 (m, 9H, arom), 5.77 (s, 2H),3.75 (t, 2H), 2.91(t, 2H). CHN 47.47, 2.65, 9.23. Found 47.34, 2.57,9.03.

EXAMPLE 68N-{5-[3-(4-bromo-2-fluoro-phenyl)-[1,2,4]-oxadiazol-5-ylmethoxy)-naphthalen-2-yl}-C,C,C-trifluoro-methanesulfonamide

The title compound was prepared from 4-bromo-2-fluoro benzoyl chlorideDMSO: δ 7.0-8.3(m, 9H, arom), 5.82 (s, 2H).

EXAMPLE 69N-{5-[3-(4-Chloro-phenyl)-[1,2,4]-oxadiazol-5-ylmethoxy)-naphthalen-2-yl}-C,C,C-trifluoro-methanesulfonamide

The title compound was prepared from 4-chloro benzoyl chloride DMSO: δ12.1 broad (s, 1H), 7.1-8.4(m, 10H, arom), 5.8 (s, 2H).

EXAMPLE 70N-{5-[3-(3′,5′-Bistrifluoromethyl-phenyl)-[1,2,4]-oxadiazol-5-ylmethoxy)-naphthalen-2-yl}-C,C,C-trifluoro-methanesulfonamide

The title compound was prepared from 3′,5′-bistrifluoromethyl benzoylchloride DMSO: δ 12.1 broad (s, 1H), 7.1-8.6(m, 9H, arom), 5.86 (s, 2H).

EXAMPLE 71N-{5-[3-(4-Trifluoromethoxy-phenyl)-[1,2,4]-oxadiazol-5-ylmethoxy)-naphthalen-2-yl}-C,C,C-trifluoro-methanesulfonamide

The title compound was prepared from 4-triflouromethoxy benzoyl chlorideDMSO: δ 11.9 (s, 1H), 7.1-8.3(m, 10H, arom), 5.84 (s, 2H).

EXAMPLE 72 N-{5-[3-(4-Methyl-phenyl)-[1,2,4]-oxadiazol-5-ylmethoxy)-naphthalen-2-yl}-C,C,C-trifluoro-methanesulfonamide

The title compound was prepared from 4-methyl benzoyl chloride DMSO: δ12.0 (s, 1H), 7.1-8.3(m, 10H, arom), 5.8 (s, 2H), 2.36 (s, 3H).

EXAMPLE 73N-{5-[3-(4-tert-Butyl-phenyl)-[1,2,4]-oxadiazol-5-ylmethoxy)-naphthalen-2-yl}-C,C,C-trifluoro-methanesulfonamide

The title compound was prepared from 4-t-butyl benzoyl chloride DMSO: δ12.1 (s, 1H), 7.1-8.3(m, 10H, arom), 5.8 (s, 2H), 1.3(s, 9H).

EXAMPLE 74 Preparation of[5-(Biphenyl-2-ylmethoxy)-naphthalen-2-yl]-urea

To 100 mg, (0.31 mmol) of the product from Example 27, step 1 in 15 mLof DMF was added 57 mg (0.50 mmol) of trimethylsilyl isocyanate thesolution was heated to 50° C. for 1.5 hr. At the end of this time it waspoured into 100 mL of water. The resulting precipitate was collected byfiltration and taken up in hot ethyl acetate. The excess water wasremoved by decantation and the solution allow to cool. Hexane wasintroduced to cloudiness and the solution allow to cool further to yield55 mg (48%) of product as a colorless solid, m.p. 159-161° C.

¹H NMR (400 MHz, DMSO) δ: 8.72 (s, 1H); 7.98 (d, J=2.0 Hz, 1H); 7.92 (d,J=9.2 Hz, 1H); 7.46 (m, 12H); 6.63 (d, J=7.2 Hz, 1H); 5.90 (s, 2H); 5.11(s, 2H).

Anal. Calcd. for C₂₄H₂₀N₂O₂: C, 78.24; H, 5.47; N, 7.60. Found: C,75.71; H, 5.68; N, 7.70; 368.4388 (+)FAB m/z 369 (M+H), 391 (M+Na).

EXAMPLE 75 [5-(4′-Methoxy-biphenyl-3-ylmethoxy)-naphthalen-2-yl]-urea

The title compound was prepared from the product obtained from Example20, step 1 using a procedure similar to EXAMPLE 74, m.p. 150 (dec.).

¹H NMR (400 MHz, DMSO) δ: 8.74 (s, 1H); 7.49 (m, 14H); 5.92 (s, 2H);5.32 (s, 2H); 3.79 (s, 3H).

Anal. Calcd. for C₂₅H₂₂N₂O₃: C, 75.36; H, 5.57; N, 7.03. Found: C,71.32; H, 5.64; N, 7.31; 398.4658 (+)ESI m/z 399 (M+H).

EXAMPLE 76[5-(4′-Chloro-4-methoxy-biphenyl-3-ylmethoxy)-naphthalen-2-yl]-urea

The title compound was prepared from the product obtained from Example21, step 1 using a procedure similar to EXAMPLE 74, m.p. 200° C. (dec.).

¹H NMR (400 MHz, DMSO) δ: 8.72 (s, 1H); 7.46 (m, 13H); 5.91 (s, 2H);5.26 (s, 2H); 3.88 (s, 3H).

Anal. Calcd. for C₂₅H₂₁ClN₂O₃: C, 69.36; H, 4.89; N, 6.47. Found: C,66.28; H, 4.54; N, 6.14; 432.9108 EI m/z 432.

EXAMPLE 77 [5-(4′-Chloro-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-urea

The title compound was prepared from the product obtained from Example22, step 1 using a procedure similar to EXAMPLE 74 m.p. 182° C. (dec.).

¹H NMR (DMSO) δ: 8.73 (s, 1H); 7.48 (m, 14H); 5.92 (s, 2H); 5.33(s, 2H).

Anal. Calcd. for C₂₄H₁₉ClN₂O₂: C, 69.14; H, 5.28; N, 8.28. Found: C,64.35; H, 4.58; N, 8.18; 402.8848 (+)FAB m/z 403 (M+H).

EXAMPLE 78N-[5-(Benzothiazol-2-ylmethoxy)-naphthalen-2-yl]-C,C,C-trifluoro-methanesulfonamide

2-amino-5-(Benzothiazol-2-ylmethoxy)-naphthalene

Sodium hydride (1.05 g) is added to a cooled solution of2-Amino-5-naphthol (4.18 g) in dimethylformamide (100 mL). Stir at roomtemperature 15 minutes and cool mixture. 2-Bromomethylbenzothiazole(6.00 g) is added and mixture to allowed to warm slowly and stir for 24hours. Remove dimethylformamide in vacuo. Redilute with ethylacetate andabsorb onto silica gel. Chromatograph (ethyl acetate/hexane) to give abrown solid (1.20 g, 15%) which was used directly in the next step.,m.p. 141-143° C. 1H NMR (DMSO-d₆, 400 MHz): d 5.43 (br s, 2H), 5.69 (s,2H), 6.72 (d, 1H), 6.80 (s, 1H), 6.95 (d, 1H), 7.12-7.20 (m, 2H), 7.45(t, 1H), 7.54 (t, 1H), 7.97 (d, 1H), 8.02 (d, 1H), 8.14 (d, 1H). MS [EI,m/z]: 306 [M]⁺. Anal. Calcd. for C₁₈H₁₄N₂OS: C, 70.56; H, 4.61; N, 9.14.Found: C, 70.38; H, 4.42; N, 9.25.

N-[5-(Benzothiazol-2-ylmethoxy)-naphthalen-2-yl]-C,C,C-trifluoro-methanesulfonamide

2-amino-5-(Benzothiazol-2-ylmethoxy)-naphthalene (0.77 g) andtriethylamine (0.35 mL) dissolved in dichloromethane (75 mL). Cool in anacetone and dry ice bath. Add triflic anhydride (0.42 mL) and allowmixture to warm to room temperature overnight. Partition between waterand ethyl acetate. Separate and dry with magnesium sulfate. Concentrateat rotovap to provide the title compound (0.450 g, 40%) as a beigesolid, m.p. 190-192° C. 1H NMR (DMSO-d₆, 400 MHz): δ 5.82 (s, 2H), 7.17(d, 1H), 7.46-7.49 (m, 3H), 7.50-7.58 (m, 2H), 7.78 (s, 1H), 8.05 (d,1H), 8.14 (d, 1H), 8.32 (d, 1H). MS [EI, m/z]: 438 [M]⁺. Anal. Calcd.for C₁₉H₁₃F₃N₂O₃S₂: C, 52.05; H, 2.99; N, 6.39. Found: C, 52.21; H,3.02; N, 6.15.

EXAMPLE 79N-[5-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)naphthalen-2-yl]C,C,C-trifluoromethanesulfonamide

5-methyl-2-phenyl-4-Chloromethyloxazole (3.34 g) is added to a chilledmixture of 2-Amino-5-naphthol (2.55 g) and sodium hydride (0.65 g) indimethylformamide (100 mL). Let stir overnight at room temperature.Concentrate in vacuo. Redilute with ethylacetate and absorb onto silicagel. Chromatograph (ethyl acetate/hexane) to give2-amino-5-(methyl-2-phenyl-oxazol-4-ylmethoxy)naphthalene (1.59 g, 30%).Without further characterization this amine and triethylamine (0.67 mL)were dissolved in dichloromethane (75 mL). Cooled in an acetone and dryice bath. Triflic anhydride (0.81 mL) was added and the mixture hadwarmed to room temperature overnight. Partition between water and ethylacetate. Separate and dry with magnesium sulfate. Concentrate atrotovap, and triturate with ethyl acetate to provide the title compound(0.70 g, 30%) as a white solid, m.p. 192-194° C. 1H NMR (DMSO-d₆, 400MHz): δ 2.49 (s, 3H), 5.21 (s, 2H), 7.17 (d, 1H), 7.36 (d, 1H), 7.46-755(m, 5H), 7.73 (s, 1H), 7.93-7.97 (m, 2H), 8.13 (d, 1H). MS [EI, m/z]:462 [M]⁺. Anal. Calcd. for C₂₂H₁₇F₃N₂O₄S 0.75(H₂O): C, 55.52; H, 3.92;N, 5.89. Found: C, 55.62; H, 4.13; N, 5.45.

EXAMPLE 80N-[5-(2-phenyl-oxazol-4-ylmethoxy)naphthalen-2-yl]C,C,C-trifluoromethanesulfonamide

Using same procedure as above 2-phenyl-4-Chloromethyloxazole was coupledwith 2-Amino-5-naphthol then reacted with triflic anhydride to providethe title compound (0.630 g, 35%) as a white solid, m.p. 195-197° C. 1HNMR (DMSO-d₆, 400 MHz): δ 5.27 (s, 2H), 7.18 (d, 1H), 7.37 (d, 1H),7.46-7.56 (m, 5H), 7.73 (s, 1H), 7.99-8.02 (d, 2H), 8.21 (d, 1H), 8.43(s, 1H). MS [EI, m/z]: 449 [M+H]⁺. Anal. Calcd. for C₂₁H₁₅F₃N₂O₄: C,56.25; H, 3.37; N, 6.25. Found: C, 56.21; H, 3.24; N, 6.22.

EXAMPLE 81N-[5-[5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-ylmethoxylnaphthalen-2-yl}C,C,C-trifluoromethanesulfonamide

Using same procedure as above5-methyl-2-(4-trifluoromethylphenyl)-4-Chloromethyloxazole was coupledwith 2-Amino-5-naphthol then reacted with triflic anhydride to providethe title compound (0.560 g, 30%) as a white solid, m.p. 212-214° C. 1HNMR (DMSO-d₆, 400 MHz): δ 2.52 (s, 3H), 5.24 (s, 2H), 7.17 (d, 1H), 7.35(d, 1H), 7.47-7.53 (m, 2H), 7.73 (s, 1H), 7.88 (d, 2H), 8.12-8.16 (m,3H). MS [EI, m/z]: 530 [M]⁺. Anal. Calcd. for C₂₃H₁₆F₆N₂O₄S: C, 52.08;H, 3.04; N, 5.28. Found: C, 52.12; H, 2.91; N, 5.17.

EXAMPLE 82N-{5-[5-methyl-2-(4-fluoro-phenyl)-oxazol-4-ylmethoxy]naphthalen-2-yl}C,C,C-trifluoromethanesulfonamide

Using same procedure as above5-methyl-2-(4-fluoro-phenyl)-4-Chloromethyloxazole was coupled with2-Amino-5-naphthol then reacted with triflic anhydride to provide thetitle compound (0.20 g, 30%) as a white solid, m.p. 178-180° C. 1H NMR(DMSO-d₆, 400 MHz): δ 2.48 (s, 3H), 5.20 (s, 2H), 7.16 (d, 1H),7.33-7.38 (m, 3H), 7.46-7.52 (m, 2H), 7.73 (s, 1H), 7.97-8.02 (m, 2H),8.13 (d, 1H). MS [EI, m/z]: 481 [M+H]⁺. Anal. Calcd. for C₂₂H₁₆F₄N₂O₄S:C, 55.00; H, 3.36; N, 5.83. Found: C, 56.70; H, 4.27; N, 5.23.

EXAMPLE 83N-[5-(Naphthalen-2-ylmethoxy)-naphthalen-2-yl]-C,C,C-trifluoro-methanesulfonamide

2-Bromomethylnaphthalene (4.60 g) is added to a mixture of2-Amino-5-naphthol (3.34 g) and sodium hydride (1.00 g) indimethylformamide (100 mL) at −40 deg. C. Let stir overnight at roomtemperature. Concentrate in vacuo. Redilute with ethylacetate and absorbonto silica gel. Chromatograph (ethyl acetate/hexane) to give2-amino-5-(Naphthalen-2-ylmethoxy)-naphthalene (1.86 g, 30%). Withoutfurther characterization this amine and triethylamine (0.90 mL) weredissolved in dichloromethane (75 mL). Cooled in an acetone and dry icebath. Triflic anhydride (1.05 mL) was added and the mixture had warmedto room temperature overnight. Partition between water and ethylacetate. Separate and dry with magnesium sulfate. Concentrate atrotovap, and triturate with ethyl acetate to provide the title compound(0.825 g, 30%) as a pale yellow solid, m.p. 140-142° C. 1H NMR (DMSO-d₆,400 MHz): δ 5.47 (s, 2H), 7.12 (d, 1H), 7.40-7.56 (m, 5H), 7.67 (d, 1H),7.75 (s, 1H), 7.91-7.98 (m, 3H), 8.09 (s, 1H), 8.30 (d, 1H). MS [EI,m/z]: 430 [M−H]⁺. Anal. Calcd. for C₂₂H₁₆F₃NO₃S: C, 61.25; H, 3.74; N,3.25. Found: C, 61.05; H, 3.81; N, 3.12.

EXAMPLE 84N-{5-[2-(4-Chloro-phenyl)-oxazol-4-ylmethoxy]naphthalen-2-yl}C,C,C-trifluoromethanesulfonamide

Using same procedure as above 2-(4-Chloro-phenyl)-4-Chloromethyloxazolewas coupled with 2-Amino-5-naphthol then reacted with triflic anhydrideto provide the title compound (0.350 g, 30%) as a white solid, m.p.198-200° C. 1H NMR (DMSO-d₆, 400 MHz): δ 5.28 (s, 2H), 7.20 (d, 1H),7.40 (d, 1H), 7.47-7.55 (m, 2H), 7.63 (d, 2H), 7.75 (s, 1H), 8.02 (d,2H), 8.22 (d, 1H), 8.47 (s, 1H). MS [EI, m/z]: 482 [M]⁺. Anal. Calcd.for C₂₁H₁₄ClF₃N₂O₄S: C, 52.24; H, 2.92; N, 5.80. Found: C, 52.45, H,3.28, N, 5.68.

EXAMPLE 85N-{5-[2-(4-tert-Butyl-phenyl)-oxazol-4-ylmethoxy]naphthalen-2-yl}C,C,C-trifluoromethanesulfonamide

Using same procedure as above2-(4-tert-Butyl-phenyl)-4-Chloromethyloxazole was coupled with2-Amino-5-naphthol then reacted with triflic anhydride to provide thetitle compound (0. 50 g, 30%) as a white solid, m.p. 165-167° C. 1H NMR(DMSO-d₆, 400 MHz): δ 1.32 (s, 9H), 5.27 (s, 2H), 7.19 (d, 1H), 7.39 (d,1H), 7.47-7.54 (m, 2H), 7.56-7.59 (d, 2H), 7.75 (s, 1H), 7.95 (d, 2H),8.22 (d, 1H), 8.41 (s, 1H). MS [EI, m/z]: 503 [M−H]⁺. Anal. Calcd. forC₂₅H₂₃F₃N₂O₄S: C, 59.52; H, 4.60; N, 5.55. Found: C, 59.23; H, 4.66; N,5.41.

EXAMPLE 86N-{5-[2-(4-Bromo-phenyl)-oxazol-4-ylmethoxy]naphthalen-2-yl}C,C,C-trifluoromethanesulfonamide

Using same procedure as above 2-(4-Bromo-phenyl)-4-Chloromethyloxazolewas coupled with 2-Amino-5-naphthol then reacted with triflic anhydrideto provide the title compound (0.25 g, 30%) as a white solid, m.p.205-207° C. 1H NMR (DMSO-d₆, 400 MHz): δ 5.28 (s, 2H), 7.19 (d, 1H),7.39 (d, 1H), 7.47-7.54 (m, 2H), 7.75 (s, 1H), 7.77 (d, 2H), 7.94 (d,2H), 8.22 (d, 1H), 8.48 (s, 1H). MS [EI, m/z]: 525 [M−H]⁺. Anal. Calcd.for C₂₁H₁₄BrF₃N₂O₄S: C, 47.83; H, 2.68; N, 5.31. Found: C, 57.66; H,2.85; N, 5.14.

EXAMPLE 87N-{5-[2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]naphthalen-2-yl}C,C,C-trifluoromethanesulfonamide

Using same procedure as above2-(4-trifluoromethyl-phenyl)-4-Chloromethyloxazole was coupled with2-Amino-5-naphthol then reacted with triflic anhydride to provide thetitle compound (0.26 g, 30%) as a white solid, m.p. 205-207° C. 1H NMR(DMSO-d₆, 400 MHz): δ 5.31 (s, 2H), 7.19 (d, 1H), 7.39 (d, 1H),7.47-7.54 (m, 2H), 7.74 (s, 1H), 7.93 (d, 2H), 8.22 (d, 2H), 8.24 (s,1H), 8.55 (s, 1H). MS [EI, m/z]: 516 [M]⁺. Anal. Calcd. forC₂₂H₁₄F₆N₂O₄S 0.5(H₂O): C, 50.25; H, 2.88; N, 5.33. Found: C, 50.39; H,2.90; N, 5.25.

EXAMPLE 88N-[5-[2-o-tolyl-oxazol-4-ylmethoxy)naphthalen-2-yl]C,C,C-trifluoromethanesulfonamide

Using same procedure as above 2-o-tolyl-4-Chloromethyloxazole wascoupled with 2-Amino-5-naphthol then reacted with triflic anhydride toprovide the title compound (0.06 g, 30%) as a pale yellow solid, m.p.127-130° C. 1H NMR (DMSO-d₆, 400 MHz): d 2.65 (s, 3H), 5.30 (s, 2H),7.23 (d, 1H), 7.34-7.45 (m, 4H), 7.47-7.55 (m, 2H), 7.75 (s, 1H), 7.95(d, 2H), 8.24 (d, 1H), 8.45 (s, 1H). MS [EI, m/z]: 461 [M−H]⁺. Anal.Calcd. for C₂₂H₁₇F₃N₂O₄S: C, 57.14; H, 3.71; N, 6.06. Found: C, 58.08;H, 3.81; N, 6.01.

1. A compound of formula (I) having the structure

wherein: Z is

Y is C═C; R₁ is selected from —SO₂CF₃, —SO₂Ar, —SO₂CH₃, —SO₂CH₂CF₃,—CONH₂, —CSNHCH₃, —CONHAr, —COAr, —COCCl₃; Ar is phenyl, naphthyl,pyridyl, or quinolyl, which may be optionally mono- or di-substitutedwith alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, halogen,hydroxyl, alkoxy of 1-6 carbon atoms, —CN, —NO₂, amino, alkylamino of1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group,thio, alkylthio of 1-6 carbon atoms, alkylsulfinyl of 1-6 carbon atoms,alkylsulfonyl of 1-6 carbon atoms, alkoxycarbonyl of 2-7 carbon atoms,alkylcarbonyl of 2-7 carbon atoms, or benzoyl; R₂ and R₃ areindependently selected from hydrogen, halogen, hydroxy, -alkoxy of 1-6carbon atoms, —CF₃, —CN, alkyl of 1-6 carbon atoms, or —CH═CHPh; or R₂and R₃ may be taken together as —C(CH₃)₂CH₂CH₂—C(CH₃)₂—, or —OCH₂CH₂O—;or R₂ and R₃ may be taken together as —CH═CH—CH═CH—, when A is not abond; R₄ is hydrogen or halogen, A is

 wherein R₆, and R₇ are each, independently, hydrogen, halo, hydroxy,alkoxy of 1-6 carbon atoms, CF₃, CN, or alkyl of 1-6 carbon atoms; or apharmaceutically acceptable salt form thereof.
 2. The compound of claim1, having the structure of formula (II):

wherein, A is

Y is —C═C—; or a pharmaceutically acceptable salt form thereof.
 3. Thecompound of claim 1, having the structure of formula (III):

or a pharmaceutically acceptable salt form thereof.
 4. The compound ofclaim 1, which is a)C,C,C-Trifluoro-N-[5-biphenyl-3-ylmethoxy)-naphthalen-2-yl]-methanesulfonamide;b)N-[5-(3′,4′-Dichloro-3-fluoro-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-C,C,C-trifluoro-methanesulfonamide;c)N-[5-(4-naphthalen-2-yl-benzyloxy-3-ylmethoxy)-naphthalen-2-yl]-C,C,C-trifluoro-methanesulfonamide;d)C,C,C-Trifluoro-N-[5-(3-fluoro-4′-trifluoromethyl-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-methanesulfonamide;e)N-[5-(4′-tert-Butyl-3-fluoro-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-C,C,C-trifluoro-methanesulfonamide;f)N-[5-(3,4′-Dichloro-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-C,C,C-trifluoro-methanesulfonamide;g)C,C,C-Trifluoro-N-[5-(3,3′,4′-trichloro-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-methanesulfonamide;or h)C,C,C-Trifluoro-N-[5-(3-fluoro-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-methanesulfonamide;or a pharmaceutically acceptable salt thereof.
 5. A method of loweringglucose levels in a mammal in need thereof which comprises providing tosaid mammal, a compound of formula (I) having the structure

wherein: Z is

Y is C═C; R₁ is selected from —SO₂CF₃, —SO₂Ar, —SO₂CH₃, —SO₂CH₂CF₃,—CONH₂, —CSNHCH₃, —CONHAr, —COAr, —COCCl₃; Ar is phenyl, naphthyl,pyridyl, or quinolyl, which may be optionally mono- or di-substitutedwith alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, halogen,hydroxyl, alkoxy of 1-6 carbon atoms, —CN, —NO₂, amino, alkylamino of1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group,thio, alkylthio of 1-6 carbon atoms, alkylsulfinyl of 1-6 carbon atoms,alkylsulfonyl of 1-6 carbon atoms, alkoxycarbonyl of 2-7 carbon atoms,alkylcarbonyl of 2-7 carbon atoms, or benzoyl; R₂ and R₃ areindependently selected from hydrogen, halogen, hydroxy, -alkoxy of 1-6carbon atoms, —CF₃, —CN, alkyl of 1-6 carbon atoms, or —CH═CHPh; or R₂and R₃ may be taken together as —C(CH₃)₂CH₂CH₂—C(CH₃)₂—, or —OCH₂CH₂O—;or R₂ and R₃ may be taken together as —CH═CH—CH═CH—, when A is not abond; R₄ is hydrogen or halogen, A is

 wherein R₆, and R₇ are each, independently, hydrogen, halo, hydroxy,alkoxy of 1-6 carbon atoms, CF₃, CN, or alkyl of 1-6 carbon atoms; or apharmaceutically acceptable salt form thereof.
 6. A method of treatingtype II diabetes in a mammal in need thereof which comprises providingto said mammal, a compound of formula (I) having the structure

wherein: Z is

Y is C═C; R₁ is selected from —SO₂CF₃, —SO₂Ar, —SO₂CH₃, —SO₂CH₂CF₃,—CONH₂, —CSNHCH₃, —CONHAr, —COAr, —COCCl₃; Ar is phenyl, naphthyl,pyridyl, or quinolyl, which may be optionally mono- or di-substitutedwith alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, halogen,hydroxyl, alkoxy of 1-6 carbon atoms, —CN, —NO₂, amino, alkylamino of1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group,thio, alkylthio of 1-6 carbon atoms, alkylsulfinyl of 1-6 carbon atoms,alkylsulfonyl of 1-6 carbon atoms, alkoxycarbonyl of 2-7 carbon atoms,alkylcarbonyl of 2-7 carbon atoms, or benzoyl; R₂ and R₃ areindependently selected from hydrogen, halogen, hydroxy, -alkoxy of 1-6carbon atoms, —CF₃, —CN, alkyl of 1-6 carbon atoms, or —CH═CHPh; or R₂and R₃ may be taken together as —C(CH₃)₂CH₂CH₂—C(CH₃)₂—, or —OCH₂CH₂O—;or R₂ and R₃ may be taken together as —CH═CH—CH═CH—, when A is not abond; R₄ is hydrogen or halogen, A is

 wherein R₆, and R₇ are each, independently, hydrogen, halo, hydroxy,alkoxy of 1-6 carbon atoms, CF₃, CN, or alkyl of 1-6 carbon atoms; or apharmaceutically acceptable salt form thereof.
 7. A method of treatingprimary hypertension in a mammal in need thereof, which comprisesproviding to said mammal a compound of formula (I) having the structure

wherein: Z is

Y is C═C; R₁ is selected from —SO₂CF₃, —SO₂Ar, —SO₂CH₃, —SO₂CH₂CF₃,—CONH₂, —CSNHCH₃, —CONHAr, —COAr, —COCCl₃; Ar is phenyl, naphthyl,pyridyl, or quinolyl, which may be optionally mono- or di-substitutedwith alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, halogen,hydroxyl, alkoxy of 1-6 carbon atoms, —CN, —NO₂, amino, alkylamino of1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group,thio, alkylthio of 1-6 carbon atoms, alkylsulfinyl of 1-6 carbon atoms,alkylsulfonyl of 1-6 carbon atoms, alkoxycarbonyl of 2-7 carbon atoms,alkylcarbonyl of 2-7 carbon atoms, or benzoyl; R₂ and R₃ areindependently selected from hydrogen, halogen, hydroxy, -alkoxy of 1-6carbon atoms, —CF₃, —CN, alkyl of 1-6 carbon atoms, or —CH═CHPh; or R₂and R₃ may be taken together as —C(CH₃)₂CH₂CH₂—C(CH₃)₂—, or —OCH₂CH₂O—;or R₂ and R₃ may be taken together as —CH═CH—CH═CH—, when A is not abond; R₄ is hydrogen or halogen, A is

 wherein R₆, and R₇ are each, independently, hydrogen, halo, hydroxy,alkoxy of 1-6 carbon atoms, CF₃, CN, or alkyl of 1-6 carbon atoms; or apharmaceutically acceptable salt form thereof; wherein the primaryhypertension is associated with the occurrence of insulin resistance ortype II diabetes in the mammal.
 8. A method of treating atherosclerosisin a mammal in need thereof, which comprises providing to said mammal acompound of formula (I) having the structure

wherein: Z is

Y is C═C; R₁ is selected from —SO₂CF₃, —SO₂Ar, —SO₂CH₃, —SO₂CH₂CF₃,—CONH₂, —CSNHCH₃, —CONHAr, —COAr, —COCCl₃; Ar is phenyl, naphthyl,pyridyl, or quinolyl, which may be optionally mono- or di-substitutedwith alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, halogen,hydroxyl, alkoxy of 1-6 carbon atoms, —CN, —NO₂, amino, alkylamino of1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group,thio, alkylthio of 1-6 carbon atoms, alkylsulfinyl of 1-6 carbon atoms,alkylsulfonyl of 1-6 carbon atoms, alkoxycarbonyl of 2-7 carbon atoms,alkylcarbonyl of 2-7 carbon atoms, or benzoyl; R₂ and R₃ areindependently selected from hydrogen, halogen, hydroxy, -alkoxy of 1-6carbon atoms, —CF₃, —CN, alkyl of 1-6 carbon atoms, or —CH═CHPh; or R₂and R₃ may be taken together as —C(CH₃)₂CH₂CH₂—C(CH₃)₂—, or —OCH₂CH₂O—;or R₂ and R₃ may be taken together as —CH═CH—CH═CH—, when A is not abond; R₄ is hydrogen or halogen, A is

 wherein R₆, and R₇ are each, independently, hydrogen, halo, hydroxy,alkoxy of 1-6 carbon atoms, CF₃, CN, or alkyl of 1-6 carbon atoms; or apharmaceutically acceptable salt form thereof; wherein theatherosclerosis is associated with the occurrence of insulin resistanceor type II diabetes in the mammal.
 9. A pharmaceutical composition whichcomprises a compound of formula (I) having the structure

wherein: Z is

Y is C═C; R₁ is selected from —SO₂CF₃, —SO₂Ar, —SO₂CH₃, —SO₂CH₂CF₃,—CONH₂, —CSNHCH₃, —CONHAr, —COAr, —COCCl₃; Ar is phenyl, naphthyl,pyridyl, or quinolyl, which may be optionally mono- or di-substitutedwith alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, halogen,hydroxyl, alkoxy of 1-6 carbon atoms, —CN, —NO₂, amino, alkylamino of1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group,thio, alkylthio of 1-6 carbon atoms, alkylsulfinyl of 1-6 carbon atoms,alkylsulfonyl of 1-6 carbon atoms, alkoxycarbonyl of 2-7 carbon atoms,alkylcarbonyl of 2-7 carbon atoms, or benzoyl; R₂ and R₃ areindependently selected from hydrogen, halogen, hydroxy, -alkoxy of 1-6carbon atoms, —CF₃, —CN, alkyl of 1-6 carbon atoms, or —CH═CHPh; or R₂and R₃ may be taken together as —C(CH₃)₂CH₂CH₂—C(CH₃)₂—, or —OCH₂CH₂O—;or R₂ and R₃ may be taken together as —CH═CH—CH═CH—, when A is not abond; R₄ is hydrogen or halogen, A is

 wherein R₆, and R₇ are each, independently, hydrogen, halo, hydroxy,alkoxy of 1-6 carbon atoms, CF₃, CN, or alkyl of 1-6 carbon atoms; or apharmaceutically acceptable salt form thereof, and a pharmaceuticalcarrier.
 10. The method of claim 5, wherein the compound has thestructure of formula (II):

wherein, A is

Y is —C═C—; or a pharmaceutically acceptable salt form thereof.
 11. Themethod of claim 5, wherein the compound has the structure of formula(III):

or a pharmaceutically acceptable salt form thereof.
 12. The method ofclaim 5, wherein the compound is: a)C,C,C-Trifluoro-N-[5-biphenyl-3-ylmethoxy)-naphthalen-2-yl]-methanesulfonamide;b)N-[5-(3′,4′-Dichloro-3-fluoro-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-C,C,C-trifluoro-methanesulfonamide;c)N-[5-(4-naphthalen-2-yl-benzyloxy-3-ylmethoxy)-naphthalen-2-yl]-C,C,C-trifluoro-methanesulfonamide;d)C,C,C-Trifluoro-N-[5-(3-fluoro-4′-trifluoromethyl-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-methanesulfonamide;e)N-[5-(4′-tert-Butyl-3-fluoro-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-C,C,C-trifluoro-methanesulfonamide;f)N-[5-(3,4′-Dichloro-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-C,C,C-trifluoro-methanesulfonamide;g)C,C,C-Trifluoro-N-[5-(3,3′,4′-trichloro-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-methanesulfonamide;or h)C,C,C-Trifluoro-N-[5-(3-fluoro-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-methanesulfonamide;or a pharmaceutically acceptable salt thereof.
 13. The method of claim6, wherein the compound has the structure of formula (II):

wherein, A is

Y is —C═C—; or a pharmaceutically acceptable salt form thereof.
 14. Themethod of claim 6, wherein the compound has the structure of formula(III):

or a pharmaceutically acceptable salt form thereof.
 15. The method ofclaim 6, wherein the compound is: a)C,C,C-Trifluoro-N-[5-biphenyl-3-ylmethoxy)-naphthalen-2-yl]-methanesulfonamide;b)N-[5-(3′,4′-Dichloro-3-fluoro-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-C,C,C-trifluoro-methanesulfonamide;c)N-[5-(4-naphthalen-2-yl-benzyloxy-3-ylmethoxy)-naphthalen-2-yl]-C,C,C-trifluoro-methanesulfonamide;d)C,C,C-Trifluoro-N-[5-(3-fluoro-4′-trifluoromethyl-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-methanesulfonamide;e)N-[5-(4′-tert-Butyl-3-fluoro-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-C,C,C-trifluoro-methanesulfonamide;f)N-[5-(3,4′-Dichloro-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-C,C,C-trifluoro-methanesulfonamide;g)C,C,C-Trifluoro-N-[5-(3,3′,4′-trichloro-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-methanesulfonamide;or h)C,C,C-Trifluoro-N-[5-(3-fluoro-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-methanesulfonamide;or a pharmaceutically acceptable salt thereof.
 16. The method of claim7, wherein the compound has the structure of formula (II):

wherein, A is

Y is —C═C—; or a pharmaceutically acceptable salt form thereof.
 17. Themethod of claim 7, wherein the compound has the structure of formula(III):

or a pharmaceutically acceptable salt form thereof.
 18. The method ofclaim 7, wherein the compound is: a)C,C,C-Trifluoro-N-[5-biphenyl-3-ylmethoxy)-naphthalen-2-yl]-methanesulfonamide;b)N-[5-(3′,4′-Dichloro-3-fluoro-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-C,C,C-trifluoro-methanesulfonamide;c)N-[5-(4-naphthalen-2-yl-benzyloxy-3-ylmethoxy)-naphthalen-2-yl]-C,C,C-trifluoro-methanesulfonamide;d)C,C,C-Trifluoro-N-[5-(3-fluoro-4′-trifluoromethyl-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-methanesulfonamide;e)N-[5-(4′-tert-Butyl-3-fluoro-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-C,C,C-trifluoro-methanesulfonamide;f)N-[5-(3,4′-Dichloro-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-C,C,C-trifluoro-methanesulfonamide;g)C,C,C-Trifluoro-N-[5-(3,3′,4′-trichloro-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-methanesulfonamide;or h)C,C,C-Trifluoro-N-[5-(3-fluoro-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-methanesulfonamide;or a pharmaceutically acceptable salt thereof.
 19. The method of claim8, wherein the compound has the structure of formula (II):

wherein, A is

Y is —C═C—; or a pharmaceutically acceptable salt form thereof.
 20. Themethod of claim 8, wherein the compound has the structure of formula(III):

or a pharmaceutically acceptable salt form thereof.
 21. The method ofclaim 8, wherein the compound is: a)C,C,C-Trifluoro-N-[5-biphenyl-3-ylmethoxy)-naphthalen-2-yl]-methanesulfonamide;b)N-[5-(3′,4′-Dichloro-3-fluoro-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-C,C,C-trifluoro-methanesulfonamide;c)N-[5-(4-naphthalen-2-yl-benzyloxy-3-ylmethoxy)-naphthalen-2-yl]-C,C,C-trifluoro-methanesulfonamide;d)C,C,C-Trifluoro-N-[5-(3-fluoro-4′-trifluoromethyl-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-methanesulfonamide;e)N-[5-(4′-tert-Butyl-3-fluoro-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-C,C,C-trifluoro-methanesulfonamide;f)N-[5-(3,4′-Dichloro-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-C,C,C-trifluoro-methanesulfonamide;g)C,C,C-Trifluoro-N-[5-(3,3′,4′-trichloro-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-methanesulfonamide;or h)C,C,C-Trifluoro-N-[5-(3-fluoro-biphenyl-4-ylmethoxy)-naphthalen-2-yl]-methanesulfonamide;or a pharmaceutically acceptable salt thereof.